MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a pivotal role in post-transcriptional gene regulation, influencing various biological processes such as cell division, proliferation, and apoptosis. Recent research has illuminated the significant involvement of miRNAs in neurological disorders, which encompass a wide range of conditions affecting both the central and peripheral nervous systems. These disorders, including neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as psychiatric conditions such as depression and schizophrenia, impose a substantial burden on global health. Dysregulated miRNAs contribute to disease pathogenesis by modulating neuronal differentiation and related signaling cascades. This review explores the biogenesis of miRNAs and their dysregulation in neurological disorders, highlighting specific miRNAs that serve as potential biomarkers and therapeutic targets. For instance, decreased levels of miR-125b-5p and miR-26b-5p in cerebrospinal fluid have been associated with Alzheimer’s disease progression. In Parkinson’s disease, distinct profiles of dysregulated miRNAs have been identified, including miR-7-5p and miR-153-3p, which target α-synuclein. Furthermore, studies have demonstrated the potential of miRNA-based therapies to modulate disease processes and improve clinical outcomes. This review critically evaluates current therapeutic strategies for miRNA delivery in neurological disorders, focusing on advanced platforms such as nanocarriers, exosomes, viral vectors, and ligand-mediated systems designed to overcome the blood-brain barrier. We also explore the future of miRNA research in the context of precision medicine, highlighting the importance of targeted delivery, safety optimization, and integration of patient-specific molecular profiles. A comprehensive understanding of miRNA-regulated networks will be essential for developing innovative diagnostics and personalized treatments for neurodegenerative and neuroinflammatory diseases.
MicroRNAs (miRNAs) are small, non-coding RNA molecules that play a pivotal role in post-transcriptional gene regulation, influencing various biological processes such as cell division, proliferation, and apoptosis. Recent research has illuminated the significant involvement of miRNAs in neurological disorders, which encompass a wide range of conditions affecting both the central and peripheral nervous systems. These disorders, including neurodegenerative diseases like Alzheimer’s and Parkinson’s, as well as psychiatric conditions such as depression and schizophrenia, impose a substantial burden on global health. Dysregulated miRNAs contribute to disease pathogenesis by modulating neuronal differentiation and related signaling cascades. This review explores the biogenesis of miRNAs and their dysregulation in neurological disorders, highlighting specific miRNAs that serve as potential biomarkers and therapeutic targets. For instance, decreased levels of miR-125b-5p and miR-26b-5p in cerebrospinal fluid have been associated with Alzheimer’s disease progression. In Parkinson’s disease, distinct profiles of dysregulated miRNAs have been identified, including miR-7-5p and miR-153-3p, which target α-synuclein. Furthermore, studies have demonstrated the potential of miRNA-based therapies to modulate disease processes and improve clinical outcomes. This review critically evaluates current therapeutic strategies for miRNA delivery in neurological disorders, focusing on advanced platforms such as nanocarriers, exosomes, viral vectors, and ligand-mediated systems designed to overcome the blood-brain barrier. We also explore the future of miRNA research in the context of precision medicine, highlighting the importance of targeted delivery, safety optimization, and integration of patient-specific molecular profiles. A comprehensive understanding of miRNA-regulated networks will be essential for developing innovative diagnostics and personalized treatments for neurodegenerative and neuroinflammatory diseases.
DOI: https://doi.org/10.37349/ent.2025.1004111
Aim:
Our previous research (Abstract, J Vessels Circ. 2021;2) suggested an increased risk of thrombotic events, including ischemic strokes, in patients with COVID-19. This study aims to determine the mortality rate and its predictors in patients with stroke and concurrent COVID-19 infection.
Methods:
A retrospective analysis was conducted on stroke patients admitted to three Iranian referral hospitals within a 3-month period during the COVID-19 pandemic (COV-pos and COV-neg groups). The mortality rate was compared to a similar period one year before the pandemic (non-COV group). The Cox proportional hazards model was used to assess the independent and interactive effects of various variables on mortality.
Results:
Among 124 stroke admissions, 59 (47.6%) had confirmed COVID-19 infection. The COV-pos group had a significantly higher initial NIHSS score (P = 0.001) compared to other groups. Mortality rates were 49.2%, 24.2%, and 17.3% in the COV-pos, COV-neg, and non-COV groups, respectively (P < 0.001). Posterior cerebral artery (PCA) stroke (HR = 65.099), internal carotid artery (ICA) stroke (HR = 19.102), and a history of diabetes mellitus (HR = 3.824) were identified as the most significant predictors of mortality in patients with stroke and COVID-19 infection.
Conclusions:
Stroke patients with COVID-19 infection exhibited a significantly higher mortality rate compared to patients without COVID-19. The type of stroke involving the PCA or ICA and a history of diabetes emerged as the strongest predictors of mortality in the studied population.
Aim:
Our previous research (Abstract, J Vessels Circ. 2021;2) suggested an increased risk of thrombotic events, including ischemic strokes, in patients with COVID-19. This study aims to determine the mortality rate and its predictors in patients with stroke and concurrent COVID-19 infection.
Methods:
A retrospective analysis was conducted on stroke patients admitted to three Iranian referral hospitals within a 3-month period during the COVID-19 pandemic (COV-pos and COV-neg groups). The mortality rate was compared to a similar period one year before the pandemic (non-COV group). The Cox proportional hazards model was used to assess the independent and interactive effects of various variables on mortality.
Results:
Among 124 stroke admissions, 59 (47.6%) had confirmed COVID-19 infection. The COV-pos group had a significantly higher initial NIHSS score (P = 0.001) compared to other groups. Mortality rates were 49.2%, 24.2%, and 17.3% in the COV-pos, COV-neg, and non-COV groups, respectively (P < 0.001). Posterior cerebral artery (PCA) stroke (HR = 65.099), internal carotid artery (ICA) stroke (HR = 19.102), and a history of diabetes mellitus (HR = 3.824) were identified as the most significant predictors of mortality in patients with stroke and COVID-19 infection.
Conclusions:
Stroke patients with COVID-19 infection exhibited a significantly higher mortality rate compared to patients without COVID-19. The type of stroke involving the PCA or ICA and a history of diabetes emerged as the strongest predictors of mortality in the studied population.
DOI: https://doi.org/10.37349/ent.2025.1004109
Neurodevelopmental disorders form a considerable group in the DSM-5, the diagnostic mental disorders manual employed in numerous regions. Some disorders are identified with biomedical tests while those from unknown sources are verified with behavioural scales. They are ubiquitous in youths, significantly impacting their behaviours and lives. They begin in early development and persist mostly throughout their lifespan with chronogeneity, i.e., changes over time. They often form comorbidities, adding to the complexity by creating “new” phenotypes at the intersection. The article aims to provide clinically critical views of ADHD and the added burden of alexithymia comorbidities with profound effects on developmental language disorder (DLD) and autism. The noted problem is the DSM-5’s mental health categorical measure of disease identification of the disorders’ symptoms, but the neglect of comorbidity. The article’s guiding theory is the adoption of the dimensional approach in addressing the target disorders, and the Vygotskian social interactional and linguistic-cognitive learning theory in proposing dimensional treatments. The ADHD including alexithymia in these disorders exhibit commonalities: 1. all are dimensional conditions rather than categorical ones requiring dimensional approaches as these include the entire continuum; 2. all show accompanying developmental language and learning limitations, and 3. all have histories of literacy acquisition problems that impact their academic trajectory while sabotaging their executive functions (EFs) development and undermining the affected individuals and the clinicians’ treatment efforts. The suggested interventions target multiple ages based on the Vygotskian social-interactional learning theory acknowledging cognitive development as language and knowledge transmitted via psychosocial interactions facilitating the internalization of education that actively forges learners’ character, psychology, and behaviours. They are meant to address their conditions’ dimensionality, remediate cognitive linguistic lags, alleviate symptoms, and substitute ineffective learning and thinking habits with more functional ones. Issues to be addressed in developing a clinical plan complete the review.
Neurodevelopmental disorders form a considerable group in the DSM-5, the diagnostic mental disorders manual employed in numerous regions. Some disorders are identified with biomedical tests while those from unknown sources are verified with behavioural scales. They are ubiquitous in youths, significantly impacting their behaviours and lives. They begin in early development and persist mostly throughout their lifespan with chronogeneity, i.e., changes over time. They often form comorbidities, adding to the complexity by creating “new” phenotypes at the intersection. The article aims to provide clinically critical views of ADHD and the added burden of alexithymia comorbidities with profound effects on developmental language disorder (DLD) and autism. The noted problem is the DSM-5’s mental health categorical measure of disease identification of the disorders’ symptoms, but the neglect of comorbidity. The article’s guiding theory is the adoption of the dimensional approach in addressing the target disorders, and the Vygotskian social interactional and linguistic-cognitive learning theory in proposing dimensional treatments. The ADHD including alexithymia in these disorders exhibit commonalities: 1. all are dimensional conditions rather than categorical ones requiring dimensional approaches as these include the entire continuum; 2. all show accompanying developmental language and learning limitations, and 3. all have histories of literacy acquisition problems that impact their academic trajectory while sabotaging their executive functions (EFs) development and undermining the affected individuals and the clinicians’ treatment efforts. The suggested interventions target multiple ages based on the Vygotskian social-interactional learning theory acknowledging cognitive development as language and knowledge transmitted via psychosocial interactions facilitating the internalization of education that actively forges learners’ character, psychology, and behaviours. They are meant to address their conditions’ dimensionality, remediate cognitive linguistic lags, alleviate symptoms, and substitute ineffective learning and thinking habits with more functional ones. Issues to be addressed in developing a clinical plan complete the review.
DOI: https://doi.org/10.37349/ent.2025.1004110
This article belongs to the special issue Advances in the Pathogenesis, Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder
Aim:
Aging and early Alzheimer’s disease (AD) affect pattern separation (PS) based mnemonic discrimination in humans. PS function involves the dentate gyrus (DG), a brain region producing new neurons during adulthood. Aging and AD presumably affect PS and DG function through different mechanisms, although it has never been clearly shown within the same study. Passive immunotherapy targeting β-amyloid peptides (Aβ) was used to determine the relative contribution of abnormal levels of Aβ to early PS deficits in two mouse models of aging and amyloid pathology, and potential involvement of adult neurogenesis.
Methods:
Female Tg2576 mice were tested in a spatial PS task from the age of three months to determine the age of onset of PS deficits. A cohort of five-month-old female Tg2576 mice and a cohort of 20-month-old male C57BL/6J mice were treated with passive immunization for four weeks, and then tested for PS performance. ELISA assays were used to quantify Aβ levels in CA3/DG regions of these mouse models. DG recruitment during PS testing was assessed with an Egr-1 ex vivo imagery. The contribution of adult-born neurons to a potential rescue of PS performances was evaluated using bromodeoxyuridine and doublecortin co-immunostainings.
Results:
Spatial PS deficits appeared first in four-month-old female Tg2576 mice, an early pre-plaque stage of Alzheimer pathology. Aβ immunotherapy restored PS performance in Tg2576 mice, but not in aged male C57BL/6J mice. PS impairments were associated with an overactivation of the DG in both models and a potentially abnormal level of immature adult-born neurons in Tg2576 mice.
Conclusions:
Alleviation of PS deficits following Aβ immunotherapy in Tg2576 mice is associated with reduced DG activation and improved adult-born neurons maturation. The absence of beneficial effects in aged mice suggests that PS deficits in aging and AD may be related to different underlying mechanisms.
Aim:
Aging and early Alzheimer’s disease (AD) affect pattern separation (PS) based mnemonic discrimination in humans. PS function involves the dentate gyrus (DG), a brain region producing new neurons during adulthood. Aging and AD presumably affect PS and DG function through different mechanisms, although it has never been clearly shown within the same study. Passive immunotherapy targeting β-amyloid peptides (Aβ) was used to determine the relative contribution of abnormal levels of Aβ to early PS deficits in two mouse models of aging and amyloid pathology, and potential involvement of adult neurogenesis.
Methods:
Female Tg2576 mice were tested in a spatial PS task from the age of three months to determine the age of onset of PS deficits. A cohort of five-month-old female Tg2576 mice and a cohort of 20-month-old male C57BL/6J mice were treated with passive immunization for four weeks, and then tested for PS performance. ELISA assays were used to quantify Aβ levels in CA3/DG regions of these mouse models. DG recruitment during PS testing was assessed with an Egr-1 ex vivo imagery. The contribution of adult-born neurons to a potential rescue of PS performances was evaluated using bromodeoxyuridine and doublecortin co-immunostainings.
Results:
Spatial PS deficits appeared first in four-month-old female Tg2576 mice, an early pre-plaque stage of Alzheimer pathology. Aβ immunotherapy restored PS performance in Tg2576 mice, but not in aged male C57BL/6J mice. PS impairments were associated with an overactivation of the DG in both models and a potentially abnormal level of immature adult-born neurons in Tg2576 mice.
Conclusions:
Alleviation of PS deficits following Aβ immunotherapy in Tg2576 mice is associated with reduced DG activation and improved adult-born neurons maturation. The absence of beneficial effects in aged mice suggests that PS deficits in aging and AD may be related to different underlying mechanisms.
DOI: https://doi.org/10.37349/ent.2025.1004108
Polyunsaturated fatty acids (PUFAs) are critical for human health, serving as key components of cellular membranes and regulators of various physiological functions. Since the body can endogenously synthesize only a small amount of these fatty acids from precursors, adequate dietary intake is essential. This article discusses the vital role of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), in fetal brain development, with maternal omega-3 intake during pregnancy linked to improved neurodevelopment and long-term cognitive outcomes. However, variability in study findings highlights the need for further research to clarify DHA’s mechanisms of action. This article explores recent findings indicating that insufficient omega-3 levels during pregnancy disrupt key neurodevelopmental processes, particularly microglial function, potentially elevating the risk of cognitive impairments and neurodevelopmental disorders, highlighting the need for further research to confirm these effects and elucidate underlying mechanisms and long-term consequences. Ensuring adequate maternal omega-3 intake is vital for supporting healthy brain development and reducing these risks. Additionally, DHA and eicosapentaenoic acid (EPA) show promise in treating pediatric depression by modulating the gut-brain axis, reducing neuroinflammation, and restoring autonomic nervous system function—mechanisms implicated in depression. While omega-3 supplementation holds potential as an adjunctive treatment for pediatric major depressive disorder (MDD), further research is necessary to refine dosing strategies and explore underlying mechanisms, ultimately advancing neuropsychiatric care.
Polyunsaturated fatty acids (PUFAs) are critical for human health, serving as key components of cellular membranes and regulators of various physiological functions. Since the body can endogenously synthesize only a small amount of these fatty acids from precursors, adequate dietary intake is essential. This article discusses the vital role of omega-3 fatty acids, particularly docosahexaenoic acid (DHA), in fetal brain development, with maternal omega-3 intake during pregnancy linked to improved neurodevelopment and long-term cognitive outcomes. However, variability in study findings highlights the need for further research to clarify DHA’s mechanisms of action. This article explores recent findings indicating that insufficient omega-3 levels during pregnancy disrupt key neurodevelopmental processes, particularly microglial function, potentially elevating the risk of cognitive impairments and neurodevelopmental disorders, highlighting the need for further research to confirm these effects and elucidate underlying mechanisms and long-term consequences. Ensuring adequate maternal omega-3 intake is vital for supporting healthy brain development and reducing these risks. Additionally, DHA and eicosapentaenoic acid (EPA) show promise in treating pediatric depression by modulating the gut-brain axis, reducing neuroinflammation, and restoring autonomic nervous system function—mechanisms implicated in depression. While omega-3 supplementation holds potential as an adjunctive treatment for pediatric major depressive disorder (MDD), further research is necessary to refine dosing strategies and explore underlying mechanisms, ultimately advancing neuropsychiatric care.
DOI: https://doi.org/10.37349/ent.2025.1004107
Background:
High-intensity training (HIT) increases walking speed for individuals with chronic stroke. Several recent studies have examined its application for those in the subacute phase following a stroke. This systematic review examines the application of HIT in the subacute phase following a stroke.
Methods:
A systematic search for studies that compared HIT (defined as 60–84% heart rate reserve or 77–93% heart rate maximum) to lower-intensity training, conventional physical therapy, placebo, or no intervention in adults 0–6 months post stroke. Randomized or quasi-randomized controlled trials, cohort studies, and case-controlled studies published in peer-reviewed journals in English were included. The primary outcome of interest was walking speed; the secondary outcome was walking endurance. Two independent evaluators performed literature selection, data extraction, and assessed study quality using the revised Cochrane risk-of-bias tool. Reporting followed PRISMA guidelines.
Results:
Of 1,642 studies initially retrieved, 10 studies with a total of 677 participants were included. All experimental groups showed an average positive change in self-selected walking speed (range: 0.20–0.56 m/s). HIT resulted in statistically significant improvements in walking speed versus comparison interventions in 4 studies. Eight studies that measured walking endurance found an average increase of 60 to 197 m following HIT.
Discussion:
HIT demonstrated superior outcomes in self-selected walking speed and walking endurance for individuals in the subacute phase post stroke, both immediately following intervention and at follow-up. These findings align with the clinical practice guideline (CPG) for chronic stroke patients. Further randomized clinical trials are needed to strengthen the evidence.
Background:
High-intensity training (HIT) increases walking speed for individuals with chronic stroke. Several recent studies have examined its application for those in the subacute phase following a stroke. This systematic review examines the application of HIT in the subacute phase following a stroke.
Methods:
A systematic search for studies that compared HIT (defined as 60–84% heart rate reserve or 77–93% heart rate maximum) to lower-intensity training, conventional physical therapy, placebo, or no intervention in adults 0–6 months post stroke. Randomized or quasi-randomized controlled trials, cohort studies, and case-controlled studies published in peer-reviewed journals in English were included. The primary outcome of interest was walking speed; the secondary outcome was walking endurance. Two independent evaluators performed literature selection, data extraction, and assessed study quality using the revised Cochrane risk-of-bias tool. Reporting followed PRISMA guidelines.
Results:
Of 1,642 studies initially retrieved, 10 studies with a total of 677 participants were included. All experimental groups showed an average positive change in self-selected walking speed (range: 0.20–0.56 m/s). HIT resulted in statistically significant improvements in walking speed versus comparison interventions in 4 studies. Eight studies that measured walking endurance found an average increase of 60 to 197 m following HIT.
Discussion:
HIT demonstrated superior outcomes in self-selected walking speed and walking endurance for individuals in the subacute phase post stroke, both immediately following intervention and at follow-up. These findings align with the clinical practice guideline (CPG) for chronic stroke patients. Further randomized clinical trials are needed to strengthen the evidence.
DOI: https://doi.org/10.37349/ent.2025.1004106
Neuroinflammation is a hallmark of various neurodegenerative and neuropsychiatric disorders, driven by complex interactions between neurotransmitter receptors and immune signaling pathways. Among these, heteroreceptor complexes—functional assemblies formed by the physical interaction of different G protein-coupled or ionotropic receptor subtypes within the same membrane microdomain—play a crucial role in modulating synaptic activity, neuroimmune responses, and inflammatory cascades. For example, the A2A-D2 receptor complex modulates dopaminergic signaling in the striatum and has been implicated in Parkinson’s disease pathology. These receptor-receptor interactions influence key signaling pathways involving dopamine, serotonin, glutamate, adenosine, and cannabinoid systems, thereby contributing to the pathophysiology of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, and depression. Dysregulation of heteroreceptor complexes disrupts neuronal homeostasis, exacerbates neuroinflammatory responses, and influences microglial and astrocytic activation. Understanding the molecular mechanisms governing these interactions, including allosteric modulation and biased agonism, offers novel therapeutic avenues for targeting neuroinflammation. Pharmacological strategies, such as selective allosteric modulators, biased agonists, and receptor-specific ligands, aim to restore heteroreceptor function and mitigate neuroinflammatory damage. Emerging clinical trials—such as those evaluating A2A receptor antagonists like istradefylline for Parkinson’s disease and 5-HT2A antagonists for schizophrenia—have shown promising neuroprotective and anti-inflammatory effects, although larger-scale, long-term studies are needed to confirm efficacy. This review highlights the pivotal role of heteroreceptor complexes in neuroinflammation, discusses their therapeutic potential, and underscores the need for further research into their functional dynamics to develop effective interventions for neurodegenerative and neuropsychiatric diseases.
Neuroinflammation is a hallmark of various neurodegenerative and neuropsychiatric disorders, driven by complex interactions between neurotransmitter receptors and immune signaling pathways. Among these, heteroreceptor complexes—functional assemblies formed by the physical interaction of different G protein-coupled or ionotropic receptor subtypes within the same membrane microdomain—play a crucial role in modulating synaptic activity, neuroimmune responses, and inflammatory cascades. For example, the A2A-D2 receptor complex modulates dopaminergic signaling in the striatum and has been implicated in Parkinson’s disease pathology. These receptor-receptor interactions influence key signaling pathways involving dopamine, serotonin, glutamate, adenosine, and cannabinoid systems, thereby contributing to the pathophysiology of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, schizophrenia, and depression. Dysregulation of heteroreceptor complexes disrupts neuronal homeostasis, exacerbates neuroinflammatory responses, and influences microglial and astrocytic activation. Understanding the molecular mechanisms governing these interactions, including allosteric modulation and biased agonism, offers novel therapeutic avenues for targeting neuroinflammation. Pharmacological strategies, such as selective allosteric modulators, biased agonists, and receptor-specific ligands, aim to restore heteroreceptor function and mitigate neuroinflammatory damage. Emerging clinical trials—such as those evaluating A2A receptor antagonists like istradefylline for Parkinson’s disease and 5-HT2A antagonists for schizophrenia—have shown promising neuroprotective and anti-inflammatory effects, although larger-scale, long-term studies are needed to confirm efficacy. This review highlights the pivotal role of heteroreceptor complexes in neuroinflammation, discusses their therapeutic potential, and underscores the need for further research into their functional dynamics to develop effective interventions for neurodegenerative and neuropsychiatric diseases.
DOI: https://doi.org/10.37349/ent.2025.1004105
This article belongs to the special issue GPCR Heteroreceptor Complexes as Key Players in Neuroprotection
Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.
Neurodegenerative diseases represent a significant and growing challenge to public health worldwide. Current therapeutic strategies often fall short in halting or reversing disease progression, highlighting the urgent need for novel approaches. Extracellular vesicles (EVs) have garnered attention as potential therapeutic agents due to their role in intercellular communication and their ability to transport bioactive cargo, including proteins, nucleic acids, and lipids. This review provides a comprehensive overview of the biology of EVs, their involvement in neurodegenerative diseases, and the potential for EV-based therapies. We discuss the different types of EVs, their biogenesis, and their cargo composition, emphasizing their relevance to neurological processes such as protein misfolding, neuroinflammation, and oxidative stress. Preclinical studies investigating EVs as carriers of therapeutic cargo and their ability to promote neuronal survival and regeneration are examined, with a focus on evidence from animal models of neurodegenerative disorders. We explore the use of EVs in the treatment of neurodegenerative diseases, including ongoing clinical trials, methods for EV isolation and modification, and future perspectives on personalized EV-based therapies designed to meet the unique needs of individual patients. Overall, this review highlights the potential of EVs as a promising avenue for neurodegenerative disease therapy, while also addressing key research gaps and translational hurdles that need to be overcome for their successful clinical implementation.
DOI: https://doi.org/10.37349/ent.2025.1004104
This article belongs to the special issue Breakthroughs in Mechanisms and Treatments for Neurodegenerative Diseases
The diagnosis of attention deficit hyperactivity disorder (ADHD) poses several diagnostic problems, as is widely acknowledged. The name points to two symptoms only, which are unspecific and embedded in many more neuropsychological symptoms. The additional deficits, such as problems with orientation, memory, cognition, emotion, autonomic nervous regulation, and motor dysfunctions, can be more important for patients in their daily lives than attention and hyperactivity. The general term “neurodevelopmental disorder (6A0)” in the International Classification of Diseases (ICD-11) is more appropriate and should be used instead. A further question is, when a dysfunction, such as inattention, becomes a clinical sign. As outlined in the International Classification of Functioning, Disability and Health (ICF), the context and the associated impairment decide on the clinical relevance of dysfunctions. Accordingly, the diagnosis of neurodevelopmental disorders must start with the description of context requirements, then assess capacity restrictions, and finally relate these to neuropsychological deficits. Subdimensions of neurodevelopmental disorders, as listed in ICD-11, are of no additional benefit, as they are comorbid merging syndromes.
The diagnosis of attention deficit hyperactivity disorder (ADHD) poses several diagnostic problems, as is widely acknowledged. The name points to two symptoms only, which are unspecific and embedded in many more neuropsychological symptoms. The additional deficits, such as problems with orientation, memory, cognition, emotion, autonomic nervous regulation, and motor dysfunctions, can be more important for patients in their daily lives than attention and hyperactivity. The general term “neurodevelopmental disorder (6A0)” in the International Classification of Diseases (ICD-11) is more appropriate and should be used instead. A further question is, when a dysfunction, such as inattention, becomes a clinical sign. As outlined in the International Classification of Functioning, Disability and Health (ICF), the context and the associated impairment decide on the clinical relevance of dysfunctions. Accordingly, the diagnosis of neurodevelopmental disorders must start with the description of context requirements, then assess capacity restrictions, and finally relate these to neuropsychological deficits. Subdimensions of neurodevelopmental disorders, as listed in ICD-11, are of no additional benefit, as they are comorbid merging syndromes.
DOI: https://doi.org/10.37349/ent.2025.1004103
This article belongs to the special issue Advances in the Pathogenesis, Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder
Chronic upper limb pain is rather common among people in general and is characterized by a complex diagnosis due to the wide variety of factors that are involved in its development. In terms of treatment, pharmacology and manual therapy have classically been the most used options. However, based on current evidence, recommendations are more inclined to apply multimodal treatments, mainly with exercise therapy and pain education, based on the patient-centered care model. This case report details the evaluation and treatment of a 23-year-old woman with chronic upper limb pain using a multimodal physical therapy with a biobehavioral approach. The intervention lasted 12 weeks with a total of 9 sessions, in which manual therapy, therapeutic exercise, pain neuroscience education, motion representation methods, and sensory retraining were applied. The treatment resulted in a substantial improvement in the patient’s health condition. This case report indicates that a multimodal physical therapy treatment based on a biobehavioral approach may offer benefits in reducing pain symptoms and enhancing somatosensory, motor-functional, and affective-cognitive abilities in patients with chronic upper limb pain, as observed in the described case. Accordingly, this treatment can be a therapeutic option for patients with chronic upper limb pain.
Chronic upper limb pain is rather common among people in general and is characterized by a complex diagnosis due to the wide variety of factors that are involved in its development. In terms of treatment, pharmacology and manual therapy have classically been the most used options. However, based on current evidence, recommendations are more inclined to apply multimodal treatments, mainly with exercise therapy and pain education, based on the patient-centered care model. This case report details the evaluation and treatment of a 23-year-old woman with chronic upper limb pain using a multimodal physical therapy with a biobehavioral approach. The intervention lasted 12 weeks with a total of 9 sessions, in which manual therapy, therapeutic exercise, pain neuroscience education, motion representation methods, and sensory retraining were applied. The treatment resulted in a substantial improvement in the patient’s health condition. This case report indicates that a multimodal physical therapy treatment based on a biobehavioral approach may offer benefits in reducing pain symptoms and enhancing somatosensory, motor-functional, and affective-cognitive abilities in patients with chronic upper limb pain, as observed in the described case. Accordingly, this treatment can be a therapeutic option for patients with chronic upper limb pain.
DOI: https://doi.org/10.37349/ent.2025.1004102
Stroke is the third leading cause of death and disability in industrialized countries. The estimated costs of stroke to the healthcare system are $85 billion in the United States and $40 billion in the European Union. Despite the extensive research over the past decades, only therapies aimed at restoring blood flow to the affected area have been successful. However, the high risk of causing intracranial hemorrhage limits the application of this type of therapy to a small number of patients. Several studies have shown that, in addition to its well-known regulatory function in erythropoiesis, erythropoietin (EPO) is a potent neuroprotective agent against ischemic stroke. However, the use of EPO to treat stroke requires long-term protocols, high doses, and multiple administrations, which may cause thromboembolic complications due to increased hematocrit and blood viscosity, making EPO treatment unsuitable. To mitigate these adverse effects, various EPO analogues with neuroprotective properties but lacking erythropoietic activity have been investigated. This review aims to provide an overview of the protective mechanisms of EPO and its derivatives in the treatment of stroke.
Stroke is the third leading cause of death and disability in industrialized countries. The estimated costs of stroke to the healthcare system are $85 billion in the United States and $40 billion in the European Union. Despite the extensive research over the past decades, only therapies aimed at restoring blood flow to the affected area have been successful. However, the high risk of causing intracranial hemorrhage limits the application of this type of therapy to a small number of patients. Several studies have shown that, in addition to its well-known regulatory function in erythropoiesis, erythropoietin (EPO) is a potent neuroprotective agent against ischemic stroke. However, the use of EPO to treat stroke requires long-term protocols, high doses, and multiple administrations, which may cause thromboembolic complications due to increased hematocrit and blood viscosity, making EPO treatment unsuitable. To mitigate these adverse effects, various EPO analogues with neuroprotective properties but lacking erythropoietic activity have been investigated. This review aims to provide an overview of the protective mechanisms of EPO and its derivatives in the treatment of stroke.
DOI: https://doi.org/10.37349/ent.2025.1004101
This article belongs to the special issue Interdisciplinary Approach to Therapeutic Strategies of Neuroprotection in Present and Future
Similar to other psychiatric disorders, drug addiction is linked to changes in neuronal activity within the mesolimbic system, which consists of dopamine (DA) neurons of the ventral tegmental area projecting to the ventral part of the striatum, the nucleus accumbens (NAc). All drugs of abuse indeed artificially increase DA concentration in the NAc, which hijacks the reward system and triggers lasting behavioral alterations, including compulsive drug-seeking and drug-taking behavior despite negative consequences and a high rate of relapse after abstinence. DA chiefly signals through DA receptor (DAR) type 1 (D1R) and type 2 (D2R), which are G protein-coupled receptor (GPCR) that are positively and negatively coupled to adenyl cyclase, respectively. Multiple evidence indicates that the potent modulatory roles of DA on other neurotransmitters and neuromodulator systems implicate the direct physical interactions (i.e., heteromerization) of DAR with other receptors. DAR heteromerization, which is increased in several preclinical models of psychiatric disorders, leads to a reciprocal and fine-tuned modulation of DAR and partner receptors, therefore suggesting that targeting DAR heteromerization may contribute to the development of clinically relevant strategies. Herein, we provide an overview of current methodologies used for detecting receptor heteromers both in heterologous systems and in situ in the brain and discuss their respective advantages and limitations. We also argue that D1R and D2R have been shown to form heteromers with multiple partner receptors in heterologous systems but only few studies were able to a provide proof of their existence in the brain or establish their biological roles. This review will emphasize on studies describing the modulation and functions of DAR heteromerization in the brain in preclinical models of psychiatric disorders, with a particular focus on addiction, a field in which those heteromerization processes have been the most extensively studied.
Similar to other psychiatric disorders, drug addiction is linked to changes in neuronal activity within the mesolimbic system, which consists of dopamine (DA) neurons of the ventral tegmental area projecting to the ventral part of the striatum, the nucleus accumbens (NAc). All drugs of abuse indeed artificially increase DA concentration in the NAc, which hijacks the reward system and triggers lasting behavioral alterations, including compulsive drug-seeking and drug-taking behavior despite negative consequences and a high rate of relapse after abstinence. DA chiefly signals through DA receptor (DAR) type 1 (D1R) and type 2 (D2R), which are G protein-coupled receptor (GPCR) that are positively and negatively coupled to adenyl cyclase, respectively. Multiple evidence indicates that the potent modulatory roles of DA on other neurotransmitters and neuromodulator systems implicate the direct physical interactions (i.e., heteromerization) of DAR with other receptors. DAR heteromerization, which is increased in several preclinical models of psychiatric disorders, leads to a reciprocal and fine-tuned modulation of DAR and partner receptors, therefore suggesting that targeting DAR heteromerization may contribute to the development of clinically relevant strategies. Herein, we provide an overview of current methodologies used for detecting receptor heteromers both in heterologous systems and in situ in the brain and discuss their respective advantages and limitations. We also argue that D1R and D2R have been shown to form heteromers with multiple partner receptors in heterologous systems but only few studies were able to a provide proof of their existence in the brain or establish their biological roles. This review will emphasize on studies describing the modulation and functions of DAR heteromerization in the brain in preclinical models of psychiatric disorders, with a particular focus on addiction, a field in which those heteromerization processes have been the most extensively studied.
DOI: https://doi.org/10.37349/ent.2025.1004100
This article belongs to the special issue GPCR Heteroreceptor Complexes as Key Players in Neuroprotection
Aim:
Growing evidence suggests that Attention Deficit Hyperactivity Disorder (ADHD) may not be a single entity with a universal remedy, but rather a group of conditions resulting from interactive bio-psycho-social factors and requiring specifically targeted interventions. ADHD research, including neurophysiology, faces inconsistent findings due to heterogeneity. This variety might indicate different physiopathogenic mechanisms. This study aimed to identify dysfunctional mechanisms behind ADHD symptoms and test if targeting these dysfunctions can improve clinical outcomes.
Methods:
230 children with ADHD diagnosis studied with hypothesis-related variables from electroencephalogram (EEG) visual inspection and quantitative z-scored power, coherence and ratios, and from event-related brain potentials (ERPs) z-sored P50, N100, N200, P300 latencies amplitudes and ratios. Parametric and non-parametric classifications were conducted on neurophysiological findings to identify clusters and design neuropsychologically-based recommended treatments (NBRTx). Treatment response evaluated thrgbrough ADHD scores comparing NBRTx with guidelines recommended treatment (GBRTx). Treatment selected by agreement between each child’s physician and the parents, both parties thoroughly informed.
Results:
Six clusters of neurophysiological findings were identified, each characterized by a combination of EEG/ERP abnormalities hypothetically related to distinct dysfunctional mechanisms. Cluster (C) findings, hypothetical dysfunction, and treatment recommendations: C1: Longer P300 latencies, hypodopaminergia: methylphenidate. C2: Centrotemporal spiles, hyperexcitable network: carbamazepine. C3: Bisynchronous spike-waves complexes, thalamocortical involvement: valproic. C4: Altered psychosis-related variables: risperidone. C5: Altered migraine-related variables: valproic. C6: Abnormal maturational interhemispheric rate: tailored psychotherapy. At 3 months, ADHD scores decreased with methylphenidate (MPH) only in C1. In other clusters children under NBRTx had good responses, those under GBRTx did not, and were switched to NBRTx with significant improvement at 6 months.
Conclusions:
Six different neurophysiological mechanisms responding to targeted interventions were identified by neurophysiological signatures. A personalized medicine approach guided by physiopathogenic mechanisms may be necessary when facing multifactorial, heterogeneous disorders such as ADHD.
Aim:
Growing evidence suggests that Attention Deficit Hyperactivity Disorder (ADHD) may not be a single entity with a universal remedy, but rather a group of conditions resulting from interactive bio-psycho-social factors and requiring specifically targeted interventions. ADHD research, including neurophysiology, faces inconsistent findings due to heterogeneity. This variety might indicate different physiopathogenic mechanisms. This study aimed to identify dysfunctional mechanisms behind ADHD symptoms and test if targeting these dysfunctions can improve clinical outcomes.
Methods:
230 children with ADHD diagnosis studied with hypothesis-related variables from electroencephalogram (EEG) visual inspection and quantitative z-scored power, coherence and ratios, and from event-related brain potentials (ERPs) z-sored P50, N100, N200, P300 latencies amplitudes and ratios. Parametric and non-parametric classifications were conducted on neurophysiological findings to identify clusters and design neuropsychologically-based recommended treatments (NBRTx). Treatment response evaluated thrgbrough ADHD scores comparing NBRTx with guidelines recommended treatment (GBRTx). Treatment selected by agreement between each child’s physician and the parents, both parties thoroughly informed.
Results:
Six clusters of neurophysiological findings were identified, each characterized by a combination of EEG/ERP abnormalities hypothetically related to distinct dysfunctional mechanisms. Cluster (C) findings, hypothetical dysfunction, and treatment recommendations: C1: Longer P300 latencies, hypodopaminergia: methylphenidate. C2: Centrotemporal spiles, hyperexcitable network: carbamazepine. C3: Bisynchronous spike-waves complexes, thalamocortical involvement: valproic. C4: Altered psychosis-related variables: risperidone. C5: Altered migraine-related variables: valproic. C6: Abnormal maturational interhemispheric rate: tailored psychotherapy. At 3 months, ADHD scores decreased with methylphenidate (MPH) only in C1. In other clusters children under NBRTx had good responses, those under GBRTx did not, and were switched to NBRTx with significant improvement at 6 months.
Conclusions:
Six different neurophysiological mechanisms responding to targeted interventions were identified by neurophysiological signatures. A personalized medicine approach guided by physiopathogenic mechanisms may be necessary when facing multifactorial, heterogeneous disorders such as ADHD.
DOI: https://doi.org/10.37349/ent.2025.100499
This article belongs to the special issue Advances in the Pathogenesis, Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder
Neurodegenerative diseases are a complex ensemble of ailments characterized by progressive neuronal deterioration and ultimate loss, resulting in drastic impairments of memory, cognition and other brain functions. These incapacitating conditions are challenging for the public health system worldwide, with unfortunately no real cure and lack of efficient drugs capable of delaying or reversing these diseases. In this context, the endocannabinoid system and exogenous cannabinoids represent an interesting field of research due to numerous studies highlighting the neuroprotective effect of cannabinoids from different sources, i.e., endogenous, phytocannabinoids, and synthetic cannabinoids. This review highlights the multilayered effects of cannabinoids and the endocannabinoid system to block the progression of neurodegeneration and minimize the deleterious effects of insults that affect the brain. We illustrate examples showing that the main effects of cannabinoids modulate different components of the brain response to these insults at the level of three major mechanisms involved in neurodegeneration: neuroinflammation, excitotoxicity, and oxidative stress.
Neurodegenerative diseases are a complex ensemble of ailments characterized by progressive neuronal deterioration and ultimate loss, resulting in drastic impairments of memory, cognition and other brain functions. These incapacitating conditions are challenging for the public health system worldwide, with unfortunately no real cure and lack of efficient drugs capable of delaying or reversing these diseases. In this context, the endocannabinoid system and exogenous cannabinoids represent an interesting field of research due to numerous studies highlighting the neuroprotective effect of cannabinoids from different sources, i.e., endogenous, phytocannabinoids, and synthetic cannabinoids. This review highlights the multilayered effects of cannabinoids and the endocannabinoid system to block the progression of neurodegeneration and minimize the deleterious effects of insults that affect the brain. We illustrate examples showing that the main effects of cannabinoids modulate different components of the brain response to these insults at the level of three major mechanisms involved in neurodegeneration: neuroinflammation, excitotoxicity, and oxidative stress.
DOI: https://doi.org/10.37349/ent.2025.100498
This article belongs to the special issue GPCR Heteroreceptor Complexes as Key Players in Neuroprotection
Aim:
This study investigates the association between ApoE genotype, plasma cholesteryl ester (CE) levels, and Alzheimer’s disease (AD) status, with a focus on CE(20:4) and CE(22:5) levels as potential indicators of lipid metabolism alterations in AD patients.
Methods:
Publicly available metabolomics data (DOI: 10.3233/JAD-215448) from 94 AD patients and 62 controls aged 55 and older were re-analyzed. CE levels were examined using non-parametric tests due to the non-normal overall data distribution. Comparisons were stratified by ApoE genotypes (ε3/ε3 and ε3/ε4).
Results:
Significant increases in CE(20:4) and CE(22:5) levels were observed in AD patients with the ApoE ε3/ε4 genotype compared to controls (p-values 0.0387 and 0.0348, respectively). No significant differences were found for other CEs or among ε3/ε3 carriers (except for sex). Overlap between CE levels in AD and control groups limits their potential as diagnostic biomarkers but underscores their role in lipid dysregulation in AD pathophysiology.
Conclusions:
Elevated CE(20:4) and CE(22:5) levels in ε3/ε4 AD patients highlight lipid metabolism alterations associated with ApoE genotype. While not providing standalone biomarkers, these findings offer insights into AD-related lipid dysregulation and warrant further investigation in high-risk ε4/ε4 carriers and therapeutic targeting of lipid metabolism.
Aim:
This study investigates the association between ApoE genotype, plasma cholesteryl ester (CE) levels, and Alzheimer’s disease (AD) status, with a focus on CE(20:4) and CE(22:5) levels as potential indicators of lipid metabolism alterations in AD patients.
Methods:
Publicly available metabolomics data (DOI: 10.3233/JAD-215448) from 94 AD patients and 62 controls aged 55 and older were re-analyzed. CE levels were examined using non-parametric tests due to the non-normal overall data distribution. Comparisons were stratified by ApoE genotypes (ε3/ε3 and ε3/ε4).
Results:
Significant increases in CE(20:4) and CE(22:5) levels were observed in AD patients with the ApoE ε3/ε4 genotype compared to controls (p-values 0.0387 and 0.0348, respectively). No significant differences were found for other CEs or among ε3/ε3 carriers (except for sex). Overlap between CE levels in AD and control groups limits their potential as diagnostic biomarkers but underscores their role in lipid dysregulation in AD pathophysiology.
Conclusions:
Elevated CE(20:4) and CE(22:5) levels in ε3/ε4 AD patients highlight lipid metabolism alterations associated with ApoE genotype. While not providing standalone biomarkers, these findings offer insights into AD-related lipid dysregulation and warrant further investigation in high-risk ε4/ε4 carriers and therapeutic targeting of lipid metabolism.
DOI: https://doi.org/10.37349/ent.2025.100497
Aim:
This study aims to investigate the effects of administering coenzyme Q10 (CoQ10) after both short-term and long-term sciatic nerve damage.
Methods:
Six groups of adult male Wistar albino rats were used. Sciatic nerve injury was performed on the rats in the short-term injury (STI) and long-term injury (LTI) groups for 15 and 60 s. For 21 days, the rats in the CoQ10, STI + CoQ10, and LTI + CoQ10 groups were also administered CoQ10 orally at a dose of 10 mg/kg of body weight; the control (Cont) group received no treatment. The nerve samples were evaluated by electrophysiology, the sciatic functional index (SFI), stereological investigations, and light and electron microscopic methods.
Results:
The number of myelinated axons was higher in the LTI group according to the Cont and the sham groups. The numbers of axons in the LTI and LTI + CoQ10 groups were higher than that in the STI and STI + CoQ10 groups. Latency and amplitude levels were significantly changed following STI and LTI treatment and CoQ10 treatment significantly improved the results following the injuries. SFI results showed highly significant differences between the Cont and STI, Cont and LTI, Cont and STI + CoQ10, STI + CoQ10 and LTI + CoQ10, and Cont and LTI + CoQ10 groups. Microscopic examinations indicated that LTI produced a significant change in the nerve structure than STI. CoQ10 ameliorated the degree of injury.
Conclusions:
Treatment with CoQ10 following sciatic nerve damage was more successful in the LTI than the STI group, and it may, therefore, effectively improve peripheral nerve regeneration, especially following LTI.
Aim:
This study aims to investigate the effects of administering coenzyme Q10 (CoQ10) after both short-term and long-term sciatic nerve damage.
Methods:
Six groups of adult male Wistar albino rats were used. Sciatic nerve injury was performed on the rats in the short-term injury (STI) and long-term injury (LTI) groups for 15 and 60 s. For 21 days, the rats in the CoQ10, STI + CoQ10, and LTI + CoQ10 groups were also administered CoQ10 orally at a dose of 10 mg/kg of body weight; the control (Cont) group received no treatment. The nerve samples were evaluated by electrophysiology, the sciatic functional index (SFI), stereological investigations, and light and electron microscopic methods.
Results:
The number of myelinated axons was higher in the LTI group according to the Cont and the sham groups. The numbers of axons in the LTI and LTI + CoQ10 groups were higher than that in the STI and STI + CoQ10 groups. Latency and amplitude levels were significantly changed following STI and LTI treatment and CoQ10 treatment significantly improved the results following the injuries. SFI results showed highly significant differences between the Cont and STI, Cont and LTI, Cont and STI + CoQ10, STI + CoQ10 and LTI + CoQ10, and Cont and LTI + CoQ10 groups. Microscopic examinations indicated that LTI produced a significant change in the nerve structure than STI. CoQ10 ameliorated the degree of injury.
Conclusions:
Treatment with CoQ10 following sciatic nerve damage was more successful in the LTI than the STI group, and it may, therefore, effectively improve peripheral nerve regeneration, especially following LTI.
DOI: https://doi.org/10.37349/ent.2025.100496
Repeat expansion diseases (REDs) are genetic disorders caused by unusual expansions of DNA sequences within certain genes. They cause several neurodegenerative diseases including Huntington’s disease (HD), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA), fragile X syndrome (FXS), and others. The pathogenic repeat expansions disrupt normal cellular processes by producing aberrant RNA repeat sequences, leading to toxic protein aggregation, RNA foci, and altered gene expression. Although they belong to the rare disease group, such diseases must be investigated to understand integral mechanisms and prevention. Current methods for alleviating these diseases involve—gene silencing therapies by antisense oligonucleotides (ASOs) and RNA interference (RNAi), CRISPR/Cas9 gene editing, small molecule therapies, etc. ASOs and RNAi reduce toxic protein production genes while CRISPR/Cas9 excise or alter expanded repeats. Small molecule therapies targeting RNA repeat-binding or proteostasis regulation are being developed to alleviate toxic protein accumulation, prevent RNA toxic foci formation, and promote the degradation of misfolded proteins. Additionally, gene replacement and regulatory element modification restore normal gene function. Some researchers tried to modulate toxic protein aggregation using heat shock proteins and chemical chaperones. This is a comprehensive review on the available research on RED treatment and their ongoing challenges, such as efficient delivery of therapies to the central nervous system, minimizing off-target effects in gene editing, sustaining therapeutic efficacy, and addressing toxicity and scalability in large-scale applications.
Repeat expansion diseases (REDs) are genetic disorders caused by unusual expansions of DNA sequences within certain genes. They cause several neurodegenerative diseases including Huntington’s disease (HD), myotonic dystrophy (DM), spinal and bulbar muscular atrophy (SBMA), fragile X syndrome (FXS), and others. The pathogenic repeat expansions disrupt normal cellular processes by producing aberrant RNA repeat sequences, leading to toxic protein aggregation, RNA foci, and altered gene expression. Although they belong to the rare disease group, such diseases must be investigated to understand integral mechanisms and prevention. Current methods for alleviating these diseases involve—gene silencing therapies by antisense oligonucleotides (ASOs) and RNA interference (RNAi), CRISPR/Cas9 gene editing, small molecule therapies, etc. ASOs and RNAi reduce toxic protein production genes while CRISPR/Cas9 excise or alter expanded repeats. Small molecule therapies targeting RNA repeat-binding or proteostasis regulation are being developed to alleviate toxic protein accumulation, prevent RNA toxic foci formation, and promote the degradation of misfolded proteins. Additionally, gene replacement and regulatory element modification restore normal gene function. Some researchers tried to modulate toxic protein aggregation using heat shock proteins and chemical chaperones. This is a comprehensive review on the available research on RED treatment and their ongoing challenges, such as efficient delivery of therapies to the central nervous system, minimizing off-target effects in gene editing, sustaining therapeutic efficacy, and addressing toxicity and scalability in large-scale applications.
DOI: https://doi.org/10.37349/ent.2024.00095
This review focuses on the current advances in the field of therapeutic targets and treatments for stroke. Stroke is a major health problem worldwide, with significant impacts on morbidity and mortality, and a considerable burden on the medical and socio-economic systems. This review provides a comprehensive overview of the current state of knowledge on acute treatments and therapeutic targets. Current stroke treatments like recanalization therapies focus mainly on restoring blood flow to the brain, reducing cell death, and preventing further damage, but have limitations in terms of efficacy and long-term outcomes. Besides acute treatments (mobile stroke units, telerehabilitation) and acute therapeutic targets, the review focuses on longer-term therapeutic targets, such as neuroprotection and neuroregeneration. Neuroprotective strategies target the mechanisms underlying energy failure, cellular acidosis, mitochondrial dysfunction, endoplasmic reticulum stress, excitotoxicity, calcium channels dysregulation, oxidative stress, neuroinflammation, blood-brain barrier disruption, apoptosis, and ischemia-reperfusion injury. Neuroregenerative approaches include stem cell therapy, gene therapy, growth factors, and rehabilitation techniques that promote the rewiring of neuronal circuits in the brain. Non-pharmacological treatments like neurostimulation and bioengineering are also presented. Additionally, we highlight the challenges and future directions in translating these therapies into clinical practice. Overall, the treatment of ischemic stroke is a complex and multifaceted process that requires a combination of acute measures as well as longer-term strategies to promote brain repair and recovery. The treatment of ischemic stroke has made significant progress in recent years with the development of new treatments and ongoing research to improve outcomes for stroke patients. However, before these therapies can be successfully integrated into routine clinical practise, further research is needed to establish standardised protocols, overcome methodological limitations, and overcome clinical challenges. By further deepening our understanding of the pathophysiology of ischemic stroke and developing innovative treatments, we can improve outcomes and quality of life for stroke survivors.
This review focuses on the current advances in the field of therapeutic targets and treatments for stroke. Stroke is a major health problem worldwide, with significant impacts on morbidity and mortality, and a considerable burden on the medical and socio-economic systems. This review provides a comprehensive overview of the current state of knowledge on acute treatments and therapeutic targets. Current stroke treatments like recanalization therapies focus mainly on restoring blood flow to the brain, reducing cell death, and preventing further damage, but have limitations in terms of efficacy and long-term outcomes. Besides acute treatments (mobile stroke units, telerehabilitation) and acute therapeutic targets, the review focuses on longer-term therapeutic targets, such as neuroprotection and neuroregeneration. Neuroprotective strategies target the mechanisms underlying energy failure, cellular acidosis, mitochondrial dysfunction, endoplasmic reticulum stress, excitotoxicity, calcium channels dysregulation, oxidative stress, neuroinflammation, blood-brain barrier disruption, apoptosis, and ischemia-reperfusion injury. Neuroregenerative approaches include stem cell therapy, gene therapy, growth factors, and rehabilitation techniques that promote the rewiring of neuronal circuits in the brain. Non-pharmacological treatments like neurostimulation and bioengineering are also presented. Additionally, we highlight the challenges and future directions in translating these therapies into clinical practice. Overall, the treatment of ischemic stroke is a complex and multifaceted process that requires a combination of acute measures as well as longer-term strategies to promote brain repair and recovery. The treatment of ischemic stroke has made significant progress in recent years with the development of new treatments and ongoing research to improve outcomes for stroke patients. However, before these therapies can be successfully integrated into routine clinical practise, further research is needed to establish standardised protocols, overcome methodological limitations, and overcome clinical challenges. By further deepening our understanding of the pathophysiology of ischemic stroke and developing innovative treatments, we can improve outcomes and quality of life for stroke survivors.
DOI: https://doi.org/10.37349/ent.2024.00094
This article belongs to the special issue Therapeutic Targets for Neuroprotection in Ischemic Stroke
Insulin-like growth factor-1 (IGF-1) elicits a variety of effects on the regulation of oxidative stress, a topic that remains shrouded in controversy. This intricate regulation plays a pivotal role in the aging process and its associated diseases. Notably, it centers around the challenge posed by endogenous antioxidant defenses, which often struggle to counteract free radicals-induced damage to various neural cell macromolecules. The interplay between IGF-1 and oxidative stress holds significant implications. Both factors are intertwined in the context of degenerative and inflammatory disruptions within the central nervous system (CNS), giving rise to dysfunctions in neurons and glial cells. These dysfunctions encompass detrimental outcomes such as excitotoxicity, neuronal attrition, and axonal impairment, all of which are closely related to behavioral irregularities. However, the complexities of IGF-1’s impact remain a topic of debate. Divergent research findings present IGF-1 as both an antioxidative agent and a catalyst to produce reactive oxygen species (ROS) in various neuropathologies. This diversity of outcomes has contributed to the ongoing controversy in the field. The present theoretical review undertakes a comprehensive vision, shedding light on the role of IGF-1 as a regulator within the mechanistic framework of oxidative stress responses. This regulatory role serves as the basis for the emergence of progressive neurodegenerative and neuroinflammatory conditions. Particularly compelling is the exploration of IGF-1 as a potential target for promising therapeutic interventions in this domain. However, the review also highlights significant limitations, including the considerations to work with this factor and the need for further research to clarify IGF-1’s role. Future perspectives should focus on refining our understanding of IGF-1’s mechanisms and exploring its therapeutic potential in more detail.
Insulin-like growth factor-1 (IGF-1) elicits a variety of effects on the regulation of oxidative stress, a topic that remains shrouded in controversy. This intricate regulation plays a pivotal role in the aging process and its associated diseases. Notably, it centers around the challenge posed by endogenous antioxidant defenses, which often struggle to counteract free radicals-induced damage to various neural cell macromolecules. The interplay between IGF-1 and oxidative stress holds significant implications. Both factors are intertwined in the context of degenerative and inflammatory disruptions within the central nervous system (CNS), giving rise to dysfunctions in neurons and glial cells. These dysfunctions encompass detrimental outcomes such as excitotoxicity, neuronal attrition, and axonal impairment, all of which are closely related to behavioral irregularities. However, the complexities of IGF-1’s impact remain a topic of debate. Divergent research findings present IGF-1 as both an antioxidative agent and a catalyst to produce reactive oxygen species (ROS) in various neuropathologies. This diversity of outcomes has contributed to the ongoing controversy in the field. The present theoretical review undertakes a comprehensive vision, shedding light on the role of IGF-1 as a regulator within the mechanistic framework of oxidative stress responses. This regulatory role serves as the basis for the emergence of progressive neurodegenerative and neuroinflammatory conditions. Particularly compelling is the exploration of IGF-1 as a potential target for promising therapeutic interventions in this domain. However, the review also highlights significant limitations, including the considerations to work with this factor and the need for further research to clarify IGF-1’s role. Future perspectives should focus on refining our understanding of IGF-1’s mechanisms and exploring its therapeutic potential in more detail.
DOI: https://doi.org/10.37349/ent.2024.00093
Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, with an unknown etiology and a multifactorial pathophysiology characterized by protein misfolding, neuroinflammation, and neuronal loss. There are three well-discussed main hypotheses for the pathophysiology of AD, which are related to i) the accumulation of amyloid β (Aβ) protein aggregates in the extracellular space, ii) deposition of hyperphosphorylated tau fragments as neurofibrillary tangles, and iii) dysregulation of hemostasis of some neurotransmitters involved in the disease, such as acetylcholine (ACh) and glutamate. The association of all these factors is responsible for installing oxidative stress and neuroinflammation, which contribute to progressive neuronal death in specific brain regions. More recently, other remarkable pathological characteristics have been described, involving changes in all levels of cellular components, especially in the action and function of protein kinases. These enzymes are crucial for cellular regulation since they play a pivotal role in the phosphorylation of protein substrates by transferring a phosphate group from the ATP molecule to threonine, serine, or tyrosine residues. In more recent studies, some kinases have been especially reported by their role in inflammatory and oxidative processes associated to AD, such as cAMP-dependent protein kinase A (PKA), cyclin-dependent protein kinase 5 (CDK5), glycogen synthase kinase 3β (GSK-3β), and the microtubule affinity regulatory kinases (MARKs). Under homeostatic conditions, protein kinases act as cellular signals, directing physiological responses, but in AD pathogenesis, these enzymes have an exacerbated activity in the brain, justifying the need for a better comprehension of their function and role, and how new kinase inhibitors could lead to innovative drugs. In this context, this brief review aimed to compile the literature data related to the most recent efforts and strategies in Medicinal Chemistry in the discovery of new kinase inhibitors, opening new ways to AD therapeutics.
Alzheimer’s disease (AD) is a progressive and incurable neurodegenerative disorder, with an unknown etiology and a multifactorial pathophysiology characterized by protein misfolding, neuroinflammation, and neuronal loss. There are three well-discussed main hypotheses for the pathophysiology of AD, which are related to i) the accumulation of amyloid β (Aβ) protein aggregates in the extracellular space, ii) deposition of hyperphosphorylated tau fragments as neurofibrillary tangles, and iii) dysregulation of hemostasis of some neurotransmitters involved in the disease, such as acetylcholine (ACh) and glutamate. The association of all these factors is responsible for installing oxidative stress and neuroinflammation, which contribute to progressive neuronal death in specific brain regions. More recently, other remarkable pathological characteristics have been described, involving changes in all levels of cellular components, especially in the action and function of protein kinases. These enzymes are crucial for cellular regulation since they play a pivotal role in the phosphorylation of protein substrates by transferring a phosphate group from the ATP molecule to threonine, serine, or tyrosine residues. In more recent studies, some kinases have been especially reported by their role in inflammatory and oxidative processes associated to AD, such as cAMP-dependent protein kinase A (PKA), cyclin-dependent protein kinase 5 (CDK5), glycogen synthase kinase 3β (GSK-3β), and the microtubule affinity regulatory kinases (MARKs). Under homeostatic conditions, protein kinases act as cellular signals, directing physiological responses, but in AD pathogenesis, these enzymes have an exacerbated activity in the brain, justifying the need for a better comprehension of their function and role, and how new kinase inhibitors could lead to innovative drugs. In this context, this brief review aimed to compile the literature data related to the most recent efforts and strategies in Medicinal Chemistry in the discovery of new kinase inhibitors, opening new ways to AD therapeutics.
DOI: https://doi.org/10.37349/ent.2024.00092
