Previous
Aim:
Childhood stress can alter adolescent stress responses, predisposing individuals to neurochemical imbalances associated with psychosis later in life. Antipsychotic treatments are limited by extrapyramidal and metabolic side effects with insignificant impact on stress-related abnormalities in schizophrenia. Flavonoids such as apigenin may offer a safer therapeutic alternative with broader neuroprotective effects. This study evaluated the effects of apigenin on serotonin and noradrenaline (NA) systems and psychotic-like behaviours in a two-hit neurodevelopmental rat model of psychosis.
Methods:
Sixty-four male rats at postnatal day (PND) 21 were assigned to either group-housed or isolation-reared conditions from PND 23–85 and divided into eight groups (n = 8). From PND 28–85, animals received saline (0.9% NaCl) or ketamine (16 mg/kg, i.p.). Apigenin (8 mg/kg, i.p.) or risperidone (0.5 mg/kg, i.p.) was administered from PND 60–85. Anxiety-like behaviour and working memory were assessed using the Elevated Plus Maze (EPM) and Y-Maze on PND 82 and 83, respectively. On PND 86, animals were sacrificed, and the amygdala, hippocampus, and prefrontal cortex were analyzed for serotonin and NA levels using ELISA (enzyme-linked immunosorbent assay).
Results:
Apigenin increased time spent and entries into the closed arms of the EPM, indicating anxiogenic effects. Although ketamine and isolation rearing produced no significant difference in the Y-maze test compared to vehicle, apigenin improved spontaneous alternation in both housing conditions. In group-housed rats, apigenin significantly (p < 0.05) increased serotonin and NA levels in the amygdala and hippocampus, while in the prefrontal, it increased serotonin levels with no significant effect on NA levels when compared to ketamine only control. In isolation-reared rats, it produced a marked increase in serotonin levels in all the examined brain regions, including increased NA levels in the amygdala with differential reduction in NA levels in both hippocampus and pre-frontal cortex when compared with ketamine control.
Conclusions:
Apigenin exerted anxiogenic effects while improving working memory and enhancing monoaminergic neurotransmission, suggesting potential therapeutic benefits for negative symptoms associated with schizophrenia.
Aim:
Childhood stress can alter adolescent stress responses, predisposing individuals to neurochemical imbalances associated with psychosis later in life. Antipsychotic treatments are limited by extrapyramidal and metabolic side effects with insignificant impact on stress-related abnormalities in schizophrenia. Flavonoids such as apigenin may offer a safer therapeutic alternative with broader neuroprotective effects. This study evaluated the effects of apigenin on serotonin and noradrenaline (NA) systems and psychotic-like behaviours in a two-hit neurodevelopmental rat model of psychosis.
Methods:
Sixty-four male rats at postnatal day (PND) 21 were assigned to either group-housed or isolation-reared conditions from PND 23–85 and divided into eight groups (n = 8). From PND 28–85, animals received saline (0.9% NaCl) or ketamine (16 mg/kg, i.p.). Apigenin (8 mg/kg, i.p.) or risperidone (0.5 mg/kg, i.p.) was administered from PND 60–85. Anxiety-like behaviour and working memory were assessed using the Elevated Plus Maze (EPM) and Y-Maze on PND 82 and 83, respectively. On PND 86, animals were sacrificed, and the amygdala, hippocampus, and prefrontal cortex were analyzed for serotonin and NA levels using ELISA (enzyme-linked immunosorbent assay).
Results:
Apigenin increased time spent and entries into the closed arms of the EPM, indicating anxiogenic effects. Although ketamine and isolation rearing produced no significant difference in the Y-maze test compared to vehicle, apigenin improved spontaneous alternation in both housing conditions. In group-housed rats, apigenin significantly (p < 0.05) increased serotonin and NA levels in the amygdala and hippocampus, while in the prefrontal, it increased serotonin levels with no significant effect on NA levels when compared to ketamine only control. In isolation-reared rats, it produced a marked increase in serotonin levels in all the examined brain regions, including increased NA levels in the amygdala with differential reduction in NA levels in both hippocampus and pre-frontal cortex when compared with ketamine control.
Conclusions:
Apigenin exerted anxiogenic effects while improving working memory and enhancing monoaminergic neurotransmission, suggesting potential therapeutic benefits for negative symptoms associated with schizophrenia.
DOI: https://doi.org/10.37349/en.2026.1006151
Targeted cancer therapies for cancer treatment are at the forefront of cancer treatments. The identification of pathologic cell signaling pathways in cancer cells via precision medicine enables the development of new therapies to target the underpinning molecular changes within tumor cells. Applying these techniques to brain tumors is no different, except for the added necessity that these therapeutics penetrate the blood-brain barrier. Besides cell signaling alterations seen in other cancers outside of the brain (such as receptor tyrosine kinase pathways, Raf/MEK/Erk pathway, PI3K/AKT/mTOR pathway, to name a few), there are several cell-signaling pathway aberrations unique to central nervous system tumors (for example isocitrate dehydrogenase mutations or O6-methylguanine DNA methyltransferase methylation status) that allow for therapies to specifically target brain tumors. Herein, we describe the various molecular pathway aberrations that have been identified and used to develop targeted molecular therapies for brain tumors.
Targeted cancer therapies for cancer treatment are at the forefront of cancer treatments. The identification of pathologic cell signaling pathways in cancer cells via precision medicine enables the development of new therapies to target the underpinning molecular changes within tumor cells. Applying these techniques to brain tumors is no different, except for the added necessity that these therapeutics penetrate the blood-brain barrier. Besides cell signaling alterations seen in other cancers outside of the brain (such as receptor tyrosine kinase pathways, Raf/MEK/Erk pathway, PI3K/AKT/mTOR pathway, to name a few), there are several cell-signaling pathway aberrations unique to central nervous system tumors (for example isocitrate dehydrogenase mutations or O6-methylguanine DNA methyltransferase methylation status) that allow for therapies to specifically target brain tumors. Herein, we describe the various molecular pathway aberrations that have been identified and used to develop targeted molecular therapies for brain tumors.
DOI: https://doi.org/10.37349/en.2026.1006150
This article belongs to the special issue Current Approaches to Malignant Tumors of the Nervous System
The protein Mitogen-activated protein kinase 9 (MAPK9) (c-Jun N-terminal kinase 2 [JNK2]) is a critical signalling molecule involved in cellular survival, inflammation, oxidative stress, and the programming of cell death. This is because there has been emerging evidence of the effects of the abnormal activation of MAPK9 in the pathogenesis and progression of neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, many medicinal plants possess multiple phytoconstituents with neuroprotective activity that can modulate the MAPK9 signalling cascade and protect neurons against injury. Thus, this review focuses on the biology and signalling pathways of MAPK9, its function in neurodegeneration, and medicinal plants and phytochemicals targeting MAPK9, together with their biological mechanism(s) of action. Recent advancements in drug design and discovery, involving computational techniques such as molecular docking, network pharmacology, and artificial intelligence, were also discussed. Additionally, current problems, limitations, and possibilities in the clinical translation of these natural compounds were highlighted. Therefore, knowledge of how these phytochemicals modulate the MAPK9 signalling pathway may offer safer, more effective preventive and therapeutic approaches for neurodegenerative disorders.
The protein Mitogen-activated protein kinase 9 (MAPK9) (c-Jun N-terminal kinase 2 [JNK2]) is a critical signalling molecule involved in cellular survival, inflammation, oxidative stress, and the programming of cell death. This is because there has been emerging evidence of the effects of the abnormal activation of MAPK9 in the pathogenesis and progression of neurodegenerative disorders like Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, many medicinal plants possess multiple phytoconstituents with neuroprotective activity that can modulate the MAPK9 signalling cascade and protect neurons against injury. Thus, this review focuses on the biology and signalling pathways of MAPK9, its function in neurodegeneration, and medicinal plants and phytochemicals targeting MAPK9, together with their biological mechanism(s) of action. Recent advancements in drug design and discovery, involving computational techniques such as molecular docking, network pharmacology, and artificial intelligence, were also discussed. Additionally, current problems, limitations, and possibilities in the clinical translation of these natural compounds were highlighted. Therefore, knowledge of how these phytochemicals modulate the MAPK9 signalling pathway may offer safer, more effective preventive and therapeutic approaches for neurodegenerative disorders.
DOI: https://doi.org/10.37349/en.2026.1006149
This article belongs to the special issue Medicinal Plants and Bioactive Phytochemicals in Neuroprotection (Vol II)
Pathogenic variants in the tumor suppressor gene NF1 cause neurofibromatosis type 1 (NF1), one of the most common hereditary cancer predisposition syndromes. Pathogenic NF1 variants have been associated with an increased risk of several cancers; however, the relationship between NF1 variation and colon cancer remains underreported. We report a 41-year-old woman with a mosaic monoallelic germline pathogenic NF1 variant, NM_000267.3:c.1756_1759del (p.Thr586Valfs*18), previously detected on germline multigene panel testing in saliva at a variant allele frequency of approximately 35%. She later presented with fatigue, dyspnea on exertion, and iron-deficiency anemia. Computed tomography, colonoscopy, biopsy, mismatch repair immunohistochemistry, surgical pathology, and tumor next-generation sequencing led to the diagnosis of right-sided colon adenocarcinoma that was mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H). She underwent right hemicolectomy, recovered postoperatively, and entered standard surveillance; at the time of manuscript development, she was also receiving systemic therapy. This case highlights the co-occurrence of an NF1 variant and dMMR colorectal cancer and underscores the need for further studies to determine whether this represents a coincidental finding or a biologically meaningful association.
Pathogenic variants in the tumor suppressor gene NF1 cause neurofibromatosis type 1 (NF1), one of the most common hereditary cancer predisposition syndromes. Pathogenic NF1 variants have been associated with an increased risk of several cancers; however, the relationship between NF1 variation and colon cancer remains underreported. We report a 41-year-old woman with a mosaic monoallelic germline pathogenic NF1 variant, NM_000267.3:c.1756_1759del (p.Thr586Valfs*18), previously detected on germline multigene panel testing in saliva at a variant allele frequency of approximately 35%. She later presented with fatigue, dyspnea on exertion, and iron-deficiency anemia. Computed tomography, colonoscopy, biopsy, mismatch repair immunohistochemistry, surgical pathology, and tumor next-generation sequencing led to the diagnosis of right-sided colon adenocarcinoma that was mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H). She underwent right hemicolectomy, recovered postoperatively, and entered standard surveillance; at the time of manuscript development, she was also receiving systemic therapy. This case highlights the co-occurrence of an NF1 variant and dMMR colorectal cancer and underscores the need for further studies to determine whether this represents a coincidental finding or a biologically meaningful association.
DOI: https://doi.org/10.37349/en.2026.1006148
The neurodegenerative condition known as Alzheimer’s disease (AD) is defined chiefly by intraneuronal tangles, large-scale neuronal death, and dementia. Although much progress has been made in Alzheimer’s research, early diagnosis of the disease and effective treatment are difficult; conventional diagnostic tests fail to detect the pathology until there is significant neurodegeneration, and many treatments do not penetrate the blood-brain barrier and have poor target specificity. Nanotechnology has the ability to completely transform neurodegenerative disease diagnosis and treatment. Sensitive molecule detection, efficient drug targeting, and integration are possible through nanotechnology-based diagnostic tools, drug delivery mechanisms, and medicines. A great deal has been achieved in the last decade with respect to this, and favorable outcomes in the therapy of AD have been witnessed. The objective of this review is to critically assess the novel potential of nanobiomaterials for early detection and treatment of AD, highlighting their contributions to sensitive biomarker detection, targeted drug delivery, multimodal imaging, and the challenges of clinical translation.
The neurodegenerative condition known as Alzheimer’s disease (AD) is defined chiefly by intraneuronal tangles, large-scale neuronal death, and dementia. Although much progress has been made in Alzheimer’s research, early diagnosis of the disease and effective treatment are difficult; conventional diagnostic tests fail to detect the pathology until there is significant neurodegeneration, and many treatments do not penetrate the blood-brain barrier and have poor target specificity. Nanotechnology has the ability to completely transform neurodegenerative disease diagnosis and treatment. Sensitive molecule detection, efficient drug targeting, and integration are possible through nanotechnology-based diagnostic tools, drug delivery mechanisms, and medicines. A great deal has been achieved in the last decade with respect to this, and favorable outcomes in the therapy of AD have been witnessed. The objective of this review is to critically assess the novel potential of nanobiomaterials for early detection and treatment of AD, highlighting their contributions to sensitive biomarker detection, targeted drug delivery, multimodal imaging, and the challenges of clinical translation.
DOI: https://doi.org/10.37349/en.2026.1006147
This article belongs to the special issue Progress in Alzheimer's disease research: etiology, molecular mechanisms involved in disease progression, and advances in therapies aimed at slowing or reversing neurodegeneration
Aim:
Neuropathic pain (NP) is common in cancer patients, but its relationship with haematological inflammatory markers remains poorly understood. This study explored the association between NP and haematological parameters in Nigerian cancer patients.
Methods:
This cross-sectional study enrolled 90 patients with solid tumours from the University of Ilorin Teaching Hospital. Pain severity was assessed using the Numerical Rating Scale, while NP was evaluated with the painDETECT questionnaire. Complete blood count parameters were analysed, and derived inflammatory indices were calculated. Statistical analyses employed chi-square tests, Spearman’s correlation, and binary logistic regression.
Results:
NP was present in 21.1% of patients. Significant associations with NP were observed for haemoglobin (p = 0.006), absolute lymphocyte count (p = 0.003), platelet-to-lymphocyte ratio (PLR, p = 0.015), haemoglobin-to-platelet ratio (HPR, p = 0.001), and systemic immune-inflammation index (SII, p < 0.001). Correlation analysis showed NP positively correlated with platelet count (ρ = 0.23, p = 0.029), absolute neutrophil count (ρ = 0.263, p = 0.012), neutrophil-to-lymphocyte ratio (NLR, ρ = 0.248, p = 0.019), SII (ρ = 0.215, p = 0.045), and neutrophil-platelet score (NPS, ρ = 0.248, p = 0.018), while correlating negatively with haemoglobin (ρ = –0.223, p = 0.034). Logistic regression identified haemoglobin, platelet count, absolute lymphocyte count, absolute neutrophil count, NLR, and HPR as independent predictors of NP.
Conclusions:
Haematological parameters reflecting systemic inflammation are significantly associated with NP in cancer patients. These readily available indices may serve as useful adjuncts for identifying at-risk patients, particularly in resource-limited settings. Prospective studies are warranted to validate these findings.
Aim:
Neuropathic pain (NP) is common in cancer patients, but its relationship with haematological inflammatory markers remains poorly understood. This study explored the association between NP and haematological parameters in Nigerian cancer patients.
Methods:
This cross-sectional study enrolled 90 patients with solid tumours from the University of Ilorin Teaching Hospital. Pain severity was assessed using the Numerical Rating Scale, while NP was evaluated with the painDETECT questionnaire. Complete blood count parameters were analysed, and derived inflammatory indices were calculated. Statistical analyses employed chi-square tests, Spearman’s correlation, and binary logistic regression.
Results:
NP was present in 21.1% of patients. Significant associations with NP were observed for haemoglobin (p = 0.006), absolute lymphocyte count (p = 0.003), platelet-to-lymphocyte ratio (PLR, p = 0.015), haemoglobin-to-platelet ratio (HPR, p = 0.001), and systemic immune-inflammation index (SII, p < 0.001). Correlation analysis showed NP positively correlated with platelet count (ρ = 0.23, p = 0.029), absolute neutrophil count (ρ = 0.263, p = 0.012), neutrophil-to-lymphocyte ratio (NLR, ρ = 0.248, p = 0.019), SII (ρ = 0.215, p = 0.045), and neutrophil-platelet score (NPS, ρ = 0.248, p = 0.018), while correlating negatively with haemoglobin (ρ = –0.223, p = 0.034). Logistic regression identified haemoglobin, platelet count, absolute lymphocyte count, absolute neutrophil count, NLR, and HPR as independent predictors of NP.
Conclusions:
Haematological parameters reflecting systemic inflammation are significantly associated with NP in cancer patients. These readily available indices may serve as useful adjuncts for identifying at-risk patients, particularly in resource-limited settings. Prospective studies are warranted to validate these findings.
DOI: https://doi.org/10.37349/en.2026.1006146
Autism spectrum disorder (ASD) is a clinically heterogeneous neurodevelopmental condition characterized by core social communication deficits and restricted/repetitive behaviors. The majority of cases present with certain medical and psychiatric comorbidities. These include epilepsy, gastrointestinal disorders, attention-deficit/hyperactivity disorder, anxiety, and metabolic dysregulation. While animal models are indispensable in pre-clinical research and studying ASD’s pathobiology, there remains a need to address these comorbidities while modelling major ASD clinical domains. The paper describes a spectrum of animal models for ASD and its comorbid disorders, with a focus on ASD & epilepsy co-occurrence.
Autism spectrum disorder (ASD) is a clinically heterogeneous neurodevelopmental condition characterized by core social communication deficits and restricted/repetitive behaviors. The majority of cases present with certain medical and psychiatric comorbidities. These include epilepsy, gastrointestinal disorders, attention-deficit/hyperactivity disorder, anxiety, and metabolic dysregulation. While animal models are indispensable in pre-clinical research and studying ASD’s pathobiology, there remains a need to address these comorbidities while modelling major ASD clinical domains. The paper describes a spectrum of animal models for ASD and its comorbid disorders, with a focus on ASD & epilepsy co-occurrence.
DOI: https://doi.org/10.37349/en.2026.1006145
This article belongs to the special issue Advances in Epilepsy Research
Epilepsy is traditionally defined by recurrent seizures arising from abnormal neuronal excitability, yet growing evidence indicates that this view is incomplete. This narrative review examines epilepsy through the framework of neural–glial network instability, an integrative perspective that places neuronal dysfunction within a broader system shaped by glial regulation, calcium dysregulation, neuroinflammatory signaling, and circuit remodeling. The review first reframes epilepsy as a disorder of progressive instability in which failures of excitation–inhibition balance, extracellular homeostasis, inflammatory restraint, and adaptive plasticity shift neural networks from compensated function toward seizure-prone states. It then synthesizes neuronal mechanisms, including excitation–inhibition imbalance, GABAergic dysfunction, and altered intrinsic excitability, together with glial mechanisms involving astrocytic regulation of ionic and neurotransmitter environments, microglial inflammatory and synaptic responses, and oligodendroglial contributions to conduction and network coordination. Calcium dysregulation is considered a cross-cutting mechanism linking excitability, intracellular stress, gliotransmission, inflammation, and long-term remodeling. The review further examines how neuroinflammation and chronic circuit reorganization help convert transient disturbances into persistent epileptic networks. Together, this framework offers a more integrated account of seizure emergence, epileptogenesis, and chronic seizure susceptibility and points toward mechanism-informed therapeutic strategies aimed at restoring durable network stability.
Epilepsy is traditionally defined by recurrent seizures arising from abnormal neuronal excitability, yet growing evidence indicates that this view is incomplete. This narrative review examines epilepsy through the framework of neural–glial network instability, an integrative perspective that places neuronal dysfunction within a broader system shaped by glial regulation, calcium dysregulation, neuroinflammatory signaling, and circuit remodeling. The review first reframes epilepsy as a disorder of progressive instability in which failures of excitation–inhibition balance, extracellular homeostasis, inflammatory restraint, and adaptive plasticity shift neural networks from compensated function toward seizure-prone states. It then synthesizes neuronal mechanisms, including excitation–inhibition imbalance, GABAergic dysfunction, and altered intrinsic excitability, together with glial mechanisms involving astrocytic regulation of ionic and neurotransmitter environments, microglial inflammatory and synaptic responses, and oligodendroglial contributions to conduction and network coordination. Calcium dysregulation is considered a cross-cutting mechanism linking excitability, intracellular stress, gliotransmission, inflammation, and long-term remodeling. The review further examines how neuroinflammation and chronic circuit reorganization help convert transient disturbances into persistent epileptic networks. Together, this framework offers a more integrated account of seizure emergence, epileptogenesis, and chronic seizure susceptibility and points toward mechanism-informed therapeutic strategies aimed at restoring durable network stability.
DOI: https://doi.org/10.37349/en.2026.1006144
This article belongs to the special issue Advances in Epilepsy Research
Traumatic brain injury (TBI) is a major cause of long-term neurological and psychiatric morbidity and is frequently associated with persistent cognitive impairment. Deficits in attention, memory, processing speed, and executive dysfunctions are among the most commonly reported cognitive sequelae and may significantly compromise everyday functioning, social integration, and quality of life. Importantly, cognitive dysfunction following TBI often co-occurs with a wide range of psychiatric manifestations, including depression, anxiety, irritability, emotional dysregulation, and post-traumatic stress symptoms, which may further exacerbate functional disability. These cognitive and psychiatric disturbances arise from complex pathophysiological processes, including diffuse axonal injury, which involves cytoskeletal disruption, axolemmal permeability changes, calcium influx, and Wallerian degeneration, and neuroinflammation, characterized by microglial M1/M2 polarization and reactive astrogliosis that alter synaptic plasticity and promote excitotoxicity. These cellular events collectively disrupt large-scale neural networks involved in cognitive control and emotional regulation, underpinning the observed deficits. This narrative review aims to provide an overview of the mechanisms underlying cognitive impairment after TBI, describe the most common clinical cognitive profiles and associated psychiatric manifestations, and discuss their implications for cognitive remediation and functional recovery. Particular attention is given to the role of cognitive rehabilitation strategies in addressing both cognitive dysfunction and functional outcomes. Emerging approaches integrating digital technologies and neuromodulation are also discussed as potential avenues to enhance rehabilitation and improve psychiatric and functional outcomes in individuals with TBI.
Traumatic brain injury (TBI) is a major cause of long-term neurological and psychiatric morbidity and is frequently associated with persistent cognitive impairment. Deficits in attention, memory, processing speed, and executive dysfunctions are among the most commonly reported cognitive sequelae and may significantly compromise everyday functioning, social integration, and quality of life. Importantly, cognitive dysfunction following TBI often co-occurs with a wide range of psychiatric manifestations, including depression, anxiety, irritability, emotional dysregulation, and post-traumatic stress symptoms, which may further exacerbate functional disability. These cognitive and psychiatric disturbances arise from complex pathophysiological processes, including diffuse axonal injury, which involves cytoskeletal disruption, axolemmal permeability changes, calcium influx, and Wallerian degeneration, and neuroinflammation, characterized by microglial M1/M2 polarization and reactive astrogliosis that alter synaptic plasticity and promote excitotoxicity. These cellular events collectively disrupt large-scale neural networks involved in cognitive control and emotional regulation, underpinning the observed deficits. This narrative review aims to provide an overview of the mechanisms underlying cognitive impairment after TBI, describe the most common clinical cognitive profiles and associated psychiatric manifestations, and discuss their implications for cognitive remediation and functional recovery. Particular attention is given to the role of cognitive rehabilitation strategies in addressing both cognitive dysfunction and functional outcomes. Emerging approaches integrating digital technologies and neuromodulation are also discussed as potential avenues to enhance rehabilitation and improve psychiatric and functional outcomes in individuals with TBI.
DOI: https://doi.org/10.37349/en.2026.1006143
Exercise is an effective non-pharmacological intervention for depressive symptoms, but the biological mechanisms underlying its intensity-dependent and symptom-specific effects remain incompletely defined. This review proposes the “lactate window” hypothesis as a testable mechanistic model, not as an established clinical prescription strategy. Lactate is a plausible candidate link because it is tightly related to exercise intensity, functions as an oxidative substrate and signaling molecule, and participates in brain energy metabolism, astrocyte-neuron metabolic coupling, neuroplasticity, neurovascular signaling, and glial-immunometabolic regulation. Major depressive disorder (MDD) is associated with altered brain energy metabolism, mitochondrial dysfunction, pH abnormalities, and disrupted glial-neuronal support, which may be particularly relevant to fatigue, anhedonia, low motivation, psychomotor slowing, and impaired effort-based decision-making. However, lactate should not be interpreted as uniformly beneficial. Preclinical work suggests that acute L-lactate can produce antidepressant-like effects, whereas human neuroimaging findings indicate that regional lactate in motivation-related cortical circuits may be associated with reduced willingness to exert physical effort. We therefore distinguish three evidence levels: established physiological findings, plausible mechanistic pathways, and hypothesis-generating clinical applications. The proposed lactate window is operationally defined by dynamic features of the response, including blood lactate peak, area under the curve (AUC), time-to-peak, clearance, recovery kinetics, an exploratory lactate-to-rating of perceived exertion (RPE) index, affective response, next-day fatigue, sleep, and adherence. The clinical goal is not to maximize lactate, but to identify a tolerable, recoverable metabolic challenge that may support adaptive brain remodeling. Future trials should test whether lactate kinetics predict antidepressant response beyond conventional exercise dose and whether such effects are strongest for energy-, motivation-, and effort-related symptom dimensions. Because direct clinical evidence in MDD remains limited, lactate-informed exercise prescription should currently be framed as a research agenda requiring prospective validation.
Exercise is an effective non-pharmacological intervention for depressive symptoms, but the biological mechanisms underlying its intensity-dependent and symptom-specific effects remain incompletely defined. This review proposes the “lactate window” hypothesis as a testable mechanistic model, not as an established clinical prescription strategy. Lactate is a plausible candidate link because it is tightly related to exercise intensity, functions as an oxidative substrate and signaling molecule, and participates in brain energy metabolism, astrocyte-neuron metabolic coupling, neuroplasticity, neurovascular signaling, and glial-immunometabolic regulation. Major depressive disorder (MDD) is associated with altered brain energy metabolism, mitochondrial dysfunction, pH abnormalities, and disrupted glial-neuronal support, which may be particularly relevant to fatigue, anhedonia, low motivation, psychomotor slowing, and impaired effort-based decision-making. However, lactate should not be interpreted as uniformly beneficial. Preclinical work suggests that acute L-lactate can produce antidepressant-like effects, whereas human neuroimaging findings indicate that regional lactate in motivation-related cortical circuits may be associated with reduced willingness to exert physical effort. We therefore distinguish three evidence levels: established physiological findings, plausible mechanistic pathways, and hypothesis-generating clinical applications. The proposed lactate window is operationally defined by dynamic features of the response, including blood lactate peak, area under the curve (AUC), time-to-peak, clearance, recovery kinetics, an exploratory lactate-to-rating of perceived exertion (RPE) index, affective response, next-day fatigue, sleep, and adherence. The clinical goal is not to maximize lactate, but to identify a tolerable, recoverable metabolic challenge that may support adaptive brain remodeling. Future trials should test whether lactate kinetics predict antidepressant response beyond conventional exercise dose and whether such effects are strongest for energy-, motivation-, and effort-related symptom dimensions. Because direct clinical evidence in MDD remains limited, lactate-informed exercise prescription should currently be framed as a research agenda requiring prospective validation.
DOI: https://doi.org/10.37349/en.2026.1006142
This article belongs to the special issue Depression: From Pathophysiology to Treatment Innovation
Psychiatric and neurological disorders represent a major global health burden, often characterized by chronic disability and incomplete response to pharmacological treatments. The emergence of long COVID has further contributed to this challenge, introducing persistent neuropsychiatric and neurological sequelae, including cognitive impairment, fatigue, mood disturbances, and autonomic dysfunction, that overlap with mechanisms observed in established brain disorders. This narrative review synthesizes current evidence on exercise as a multimodal therapeutic strategy for individuals with long COVID and pre-existing or COVID-related psychiatric and neurological conditions. Exercise may exert broad effects across interconnected biological systems, potentially enhancing neuroplasticity and neurotrophic signaling, modulating neuroinflammation and immune responses, improving mitochondrial function and energy metabolism, supporting cerebrovascular health, regulating stress physiology and autonomic balance, and influencing the gut–brain axis. These mechanisms are thought to converge on shared pathophysiological pathways implicated in depression, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, neurodegenerative diseases, stroke, epilepsy, and post-viral syndromes. Clinical evidence suggests that structured, individualized, and supervised exercise programs may improve mood, cognition, mobility, fatigue, and quality of life. However, careful pacing and symptom-contingent adaptation are essential in long COVID to avoid post-exertional symptom exacerbation. Although high-quality randomized trials remain limited, exercise appears to be a promising, low-risk, and potentially scalable component of multidisciplinary rehabilitation in long COVID-related brain disorders.
Psychiatric and neurological disorders represent a major global health burden, often characterized by chronic disability and incomplete response to pharmacological treatments. The emergence of long COVID has further contributed to this challenge, introducing persistent neuropsychiatric and neurological sequelae, including cognitive impairment, fatigue, mood disturbances, and autonomic dysfunction, that overlap with mechanisms observed in established brain disorders. This narrative review synthesizes current evidence on exercise as a multimodal therapeutic strategy for individuals with long COVID and pre-existing or COVID-related psychiatric and neurological conditions. Exercise may exert broad effects across interconnected biological systems, potentially enhancing neuroplasticity and neurotrophic signaling, modulating neuroinflammation and immune responses, improving mitochondrial function and energy metabolism, supporting cerebrovascular health, regulating stress physiology and autonomic balance, and influencing the gut–brain axis. These mechanisms are thought to converge on shared pathophysiological pathways implicated in depression, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, neurodegenerative diseases, stroke, epilepsy, and post-viral syndromes. Clinical evidence suggests that structured, individualized, and supervised exercise programs may improve mood, cognition, mobility, fatigue, and quality of life. However, careful pacing and symptom-contingent adaptation are essential in long COVID to avoid post-exertional symptom exacerbation. Although high-quality randomized trials remain limited, exercise appears to be a promising, low-risk, and potentially scalable component of multidisciplinary rehabilitation in long COVID-related brain disorders.
DOI: https://doi.org/10.37349/en.2026.1006141
Aim:
To investigate the mechanisms underlying MK-801-induced schizophrenia-like cognitive dysfunction by examining the interplay between brain interstitial fluid (ISF) drainage impairment, myelin structural integrity, and regional neurometabolic disturbances.
Methods:
Mice received chronic administration of MK-801 (2 mg/kg/day) for two weeks to induce schizophrenia-like phenotypes. Cognitive function and sensorimotor gating were evaluated using the novel object recognition test and pre-pulse inhibition (PPI) assessment. ISF drainage patterns were visualized via fluorescent tracing with Lucifer Yellow. Myelin integrity in the internal capsule was quantified using Luxol Fast Blue (LFB) staining and transmission electron microscopy (TEM). Regional metabolic profiles in the caudate nucleus and thalamus were analyzed using untargeted metabolomics.
Results:
MK-801 treatment resulted in significant recognition memory impairment and sensorimotor gating deficits. Fluorescent tracing revealed pathological ISF reflux from the caudate nucleus toward the thalamus, which was restricted in control mice. This drainage failure corresponded to severe demyelination and ultrastructural damage in the internal capsule, characterized by increased myelin thickness and a significantly decreased G-ratio. Furthermore, regional metabolomic analysis identified distinct dysregulation of tryptophan metabolism in the caudate nucleus and tyrosine metabolism in the thalamus.
Conclusions:
Myelin degradation in the internal capsule disrupts the structural barrier required for compartmentalized ISF drainage. The resulting ISF reflux facilitates regional metabolic imbalances, particularly within tryptophan and tyrosine pathways, suggesting that fluidic dynamics failure is a critical contributor to the neurochemical pathology of schizophrenia.
Aim:
To investigate the mechanisms underlying MK-801-induced schizophrenia-like cognitive dysfunction by examining the interplay between brain interstitial fluid (ISF) drainage impairment, myelin structural integrity, and regional neurometabolic disturbances.
Methods:
Mice received chronic administration of MK-801 (2 mg/kg/day) for two weeks to induce schizophrenia-like phenotypes. Cognitive function and sensorimotor gating were evaluated using the novel object recognition test and pre-pulse inhibition (PPI) assessment. ISF drainage patterns were visualized via fluorescent tracing with Lucifer Yellow. Myelin integrity in the internal capsule was quantified using Luxol Fast Blue (LFB) staining and transmission electron microscopy (TEM). Regional metabolic profiles in the caudate nucleus and thalamus were analyzed using untargeted metabolomics.
Results:
MK-801 treatment resulted in significant recognition memory impairment and sensorimotor gating deficits. Fluorescent tracing revealed pathological ISF reflux from the caudate nucleus toward the thalamus, which was restricted in control mice. This drainage failure corresponded to severe demyelination and ultrastructural damage in the internal capsule, characterized by increased myelin thickness and a significantly decreased G-ratio. Furthermore, regional metabolomic analysis identified distinct dysregulation of tryptophan metabolism in the caudate nucleus and tyrosine metabolism in the thalamus.
Conclusions:
Myelin degradation in the internal capsule disrupts the structural barrier required for compartmentalized ISF drainage. The resulting ISF reflux facilitates regional metabolic imbalances, particularly within tryptophan and tyrosine pathways, suggesting that fluidic dynamics failure is a critical contributor to the neurochemical pathology of schizophrenia.
DOI: https://doi.org/10.37349/en.2026.1006140
Type 2 diabetes continues to grow in prevalence globally due to contemporary dietary patterns and physical inactivity. Among its multiple complications, neurological injury is a long-known consequence of diabetes, especially in the peripheral nerve as diabetic peripheral neuropathy. However, the adverse effects of diabetes on brain health are also increasingly appreciated, raising patients’ risk of developing cognitive impairment and eventual dementia along with brain structural changes. Thus, despite the highly heritable nature of Alzheimer’s disease, addressing modifiable risk factors, including type 2 diabetes, may help curb dementia development. This review covers epidemiological evidence for the link between diabetes and dementia as well as mechanistic evidence on similar underlying pathophysiological pathways, describing potential links between the two diseases. Given excess dementia risk from diabetes, this review also covers how optimal diabetes control and, ideally, diabetes prevention, may mitigate future dementia burden, concluding with some practical interventions.
Type 2 diabetes continues to grow in prevalence globally due to contemporary dietary patterns and physical inactivity. Among its multiple complications, neurological injury is a long-known consequence of diabetes, especially in the peripheral nerve as diabetic peripheral neuropathy. However, the adverse effects of diabetes on brain health are also increasingly appreciated, raising patients’ risk of developing cognitive impairment and eventual dementia along with brain structural changes. Thus, despite the highly heritable nature of Alzheimer’s disease, addressing modifiable risk factors, including type 2 diabetes, may help curb dementia development. This review covers epidemiological evidence for the link between diabetes and dementia as well as mechanistic evidence on similar underlying pathophysiological pathways, describing potential links between the two diseases. Given excess dementia risk from diabetes, this review also covers how optimal diabetes control and, ideally, diabetes prevention, may mitigate future dementia burden, concluding with some practical interventions.
DOI: https://doi.org/10.37349/en.2026.1006139
This article belongs to the special issue Progress in Alzheimer's disease research: etiology, molecular mechanisms involved in disease progression, and advances in therapies aimed at slowing or reversing neurodegeneration
The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) started in 2010 to study the effect of healthy adult ageing on cognition and the brain in a population-derived sample. The study design and protocol for Phases 1–3 of Cam-CAN were detailed in 10.1186/s12883-014-0204-1; this paper outlines the design and protocol of Phases 4–5, which enable longitudinal investigation of cognitive and brain ageing over approximately 12 years. More details about the Cam-CAN project can be found here: www.cam-can.org. Phase 4 was an at-home assessment of cognition, demographics and lifestyle, performed approximately 6 years after Phase 1 (baseline assessment), for which all people from Phase 1 were invited. Phase 5 combined repeated online cognitive, demographics and lifestyle assessment, followed by in-lab attendance for MRI and MEG brain scanning, approximately 12 years after Phase 1, for which all people from Phase 2 (baseline brain assessment) were invited. Demographics, lifestyle and cognitive data are therefore now available for three timepoints, and MRI and MEG brain data for two timepoints. The Cam-CAN study offers deep and wide phenotyping of neurocognitive health across the adult lifespan (18–96). These rich data will allow researchers to address questions like: why do some people maintain their cognitive abilities better than others, in terms of their brain structure or function, their lifestyle and/or their genetics? Given the shifting demographics towards old age in most countries, this knowledge will be important to help people function independently for longer, reducing both individual and societal burden.
The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) started in 2010 to study the effect of healthy adult ageing on cognition and the brain in a population-derived sample. The study design and protocol for Phases 1–3 of Cam-CAN were detailed in 10.1186/s12883-014-0204-1; this paper outlines the design and protocol of Phases 4–5, which enable longitudinal investigation of cognitive and brain ageing over approximately 12 years. More details about the Cam-CAN project can be found here: www.cam-can.org. Phase 4 was an at-home assessment of cognition, demographics and lifestyle, performed approximately 6 years after Phase 1 (baseline assessment), for which all people from Phase 1 were invited. Phase 5 combined repeated online cognitive, demographics and lifestyle assessment, followed by in-lab attendance for MRI and MEG brain scanning, approximately 12 years after Phase 1, for which all people from Phase 2 (baseline brain assessment) were invited. Demographics, lifestyle and cognitive data are therefore now available for three timepoints, and MRI and MEG brain data for two timepoints. The Cam-CAN study offers deep and wide phenotyping of neurocognitive health across the adult lifespan (18–96). These rich data will allow researchers to address questions like: why do some people maintain their cognitive abilities better than others, in terms of their brain structure or function, their lifestyle and/or their genetics? Given the shifting demographics towards old age in most countries, this knowledge will be important to help people function independently for longer, reducing both individual and societal burden.
DOI: https://doi.org/10.37349/en.2026.1006138
Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has gained great attention for its neuroprotective properties, especially for Alzheimer’s disease (AD), which is a progressive neurodegenerative disorder with limited therapeutic options. This review provides several experimental evidence on the effects of TQ in AD models. The evidences indicate that TQ reduces the amyloid-β accumulation, reduces the oxidative stress and neuroinflammation, and improves cognitive and behavioral outcomes. Additionally, TQ should be able to promote the neuronal survival and neurogenesis while reducing biological markers that indicate brain damage or neuron loss. Although these findings clearly highlight and show the promising therapeutic potential of the TQ molecule in the AD, it is important to note that further in-depth studies are still needed to fully understand its underlying molecular mechanisms and to determine its clinical relevance in patients.
Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has gained great attention for its neuroprotective properties, especially for Alzheimer’s disease (AD), which is a progressive neurodegenerative disorder with limited therapeutic options. This review provides several experimental evidence on the effects of TQ in AD models. The evidences indicate that TQ reduces the amyloid-β accumulation, reduces the oxidative stress and neuroinflammation, and improves cognitive and behavioral outcomes. Additionally, TQ should be able to promote the neuronal survival and neurogenesis while reducing biological markers that indicate brain damage or neuron loss. Although these findings clearly highlight and show the promising therapeutic potential of the TQ molecule in the AD, it is important to note that further in-depth studies are still needed to fully understand its underlying molecular mechanisms and to determine its clinical relevance in patients.
DOI: https://doi.org/10.37349/en.2026.1006137
This article belongs to the special issue Medicinal Plants and Bioactive Phytochemicals in Neuroprotection (Vol II)
For this review paper, data on protein misfolding and aggregation in progressive myoclonus epilepsies and some developmental encephalopathies are gathered. There is evidence that in some cases of monogenic epilepsies, misfolding of the mutated protein takes place, often leading to protein aggregation. On one hand, protein aggregation reduces the amount of protein and its activity; on the other, it exerts generic toxicity to neurons. Understanding the molecular causes due to loss of normal function and gain of toxic function of the mutated aggregate-prone proteins is important to obtain new therapies. By observing the symptomatology of progressive and developmental epileptic syndromes, one can derive some conclusions about the relevance of protein misfolding and aggregation in the picture. A plausible view seems that the most severe symptoms of dementia, behavioral and psychiatric symptoms, are linked to protein aggregation and downstream effects on cellular degradation and energy systems. Finally, I discuss the potential of targeting the proteostasis network to develop novel anti-seizure and neuroprotective therapies.
For this review paper, data on protein misfolding and aggregation in progressive myoclonus epilepsies and some developmental encephalopathies are gathered. There is evidence that in some cases of monogenic epilepsies, misfolding of the mutated protein takes place, often leading to protein aggregation. On one hand, protein aggregation reduces the amount of protein and its activity; on the other, it exerts generic toxicity to neurons. Understanding the molecular causes due to loss of normal function and gain of toxic function of the mutated aggregate-prone proteins is important to obtain new therapies. By observing the symptomatology of progressive and developmental epileptic syndromes, one can derive some conclusions about the relevance of protein misfolding and aggregation in the picture. A plausible view seems that the most severe symptoms of dementia, behavioral and psychiatric symptoms, are linked to protein aggregation and downstream effects on cellular degradation and energy systems. Finally, I discuss the potential of targeting the proteostasis network to develop novel anti-seizure and neuroprotective therapies.
DOI: https://doi.org/10.37349/en.2026.1006136
This article belongs to the special issue Advances in Epilepsy Research
Aim:
Redox-oxidative dysregulation is implicated in the aetiology of several diseases, including schizophrenia, with a possible influence on clinical symptoms. This study investigated the influence of redox, lipid peroxidation, and micronutrient antioxidants on the expression of clinical phenotypes of schizophrenia.
Methods:
A total of 220 consenting drug-naïve volunteers, including 120 participants with schizophrenia and 100 apparently healthy controls, were recruited. Schizophrenia symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Lipid peroxidation (malondialdehyde; MDA) was quantified using the thiobarbituric acid reactive substances (TBARS) spectrophotometric method; glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were assessed using established enzymatic activity assays; total antioxidant capacity (TAC) was determined by the phosphomolybdenum colorimetric method; vitamins C and E were measured using spectrophotometric biochemical assays; and zinc (Zn) and selenium (Se) concentrations were quantified using atomic absorption spectrophotometry (AAS).
Results:
Enzymatic antioxidants, SOD (19.58 ± 0.80; 10.12 ± 0.45 U/L) and CAT (41.73 ± 1.81; 21.33 ± 0.98 U/L), increased in schizophrenia compared with controls (p < 0.05), but decreased non-enzymatic antioxidants; GSH (14.5 ± 0.28; 15.9 ± 1.59 µmol/L, p < 0.05). Furthermore, serum levels of zinc (1.8 ± 0.01; 2.7 ± 0.02 mg/L), selenium (0.08 ± 0.01; 0.10 ± 0.01 mg/L), and vitamin C (12.98 ± 0.49; 15.08 ± 0.37 mg/L) were lowered in schizophrenia compared with controls (p < 0.05). GSH had a negative correlation with positive symptoms (r = –0.285, p = 0.013) while SOD (r = 0.281, p = 0.001) and CAT (r = 0.179, p = 0.034) correlated positively with MDA (p < 0.05). In contrast, GSH (r = –0.247, p = 0.003) and TAC (r = –0.221, p = 0.009) correlated negatively with MDA (p < 0.05).
Conclusions:
Drug-naïve Nigerian individuals with schizophrenia appear to exhibit a pattern of redox imbalance, including increased lipid peroxidation, altered antioxidant enzyme activity, and reduced non-enzymatic antioxidants, with lower GSH levels modestly associated with greater positive symptom severity.
Aim:
Redox-oxidative dysregulation is implicated in the aetiology of several diseases, including schizophrenia, with a possible influence on clinical symptoms. This study investigated the influence of redox, lipid peroxidation, and micronutrient antioxidants on the expression of clinical phenotypes of schizophrenia.
Methods:
A total of 220 consenting drug-naïve volunteers, including 120 participants with schizophrenia and 100 apparently healthy controls, were recruited. Schizophrenia symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS). Lipid peroxidation (malondialdehyde; MDA) was quantified using the thiobarbituric acid reactive substances (TBARS) spectrophotometric method; glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) were assessed using established enzymatic activity assays; total antioxidant capacity (TAC) was determined by the phosphomolybdenum colorimetric method; vitamins C and E were measured using spectrophotometric biochemical assays; and zinc (Zn) and selenium (Se) concentrations were quantified using atomic absorption spectrophotometry (AAS).
Results:
Enzymatic antioxidants, SOD (19.58 ± 0.80; 10.12 ± 0.45 U/L) and CAT (41.73 ± 1.81; 21.33 ± 0.98 U/L), increased in schizophrenia compared with controls (p < 0.05), but decreased non-enzymatic antioxidants; GSH (14.5 ± 0.28; 15.9 ± 1.59 µmol/L, p < 0.05). Furthermore, serum levels of zinc (1.8 ± 0.01; 2.7 ± 0.02 mg/L), selenium (0.08 ± 0.01; 0.10 ± 0.01 mg/L), and vitamin C (12.98 ± 0.49; 15.08 ± 0.37 mg/L) were lowered in schizophrenia compared with controls (p < 0.05). GSH had a negative correlation with positive symptoms (r = –0.285, p = 0.013) while SOD (r = 0.281, p = 0.001) and CAT (r = 0.179, p = 0.034) correlated positively with MDA (p < 0.05). In contrast, GSH (r = –0.247, p = 0.003) and TAC (r = –0.221, p = 0.009) correlated negatively with MDA (p < 0.05).
Conclusions:
Drug-naïve Nigerian individuals with schizophrenia appear to exhibit a pattern of redox imbalance, including increased lipid peroxidation, altered antioxidant enzyme activity, and reduced non-enzymatic antioxidants, with lower GSH levels modestly associated with greater positive symptom severity.
DOI: https://doi.org/10.37349/en.2026.1006134
Aim:
Stroke represents a leading cause of mortality and disability globally, yet comprehensive epidemiological analyses for Saudi Arabia remain limited. This study aimed to analyze temporal trends in stroke incidence, mortality, and disability-adjusted life years (DALYs) in Saudi Arabia from 1990 to 2021, examine stroke subtype distributions and risk factor attributions, and compare findings with regional and international benchmarks.
Methods:
We conducted a comprehensive analysis of the Global Burden of Disease (GBD) 2021 study data for Saudi Arabia, supplemented by systematic review findings and hospital-based registry data. Age-standardized incidence rates (ASIRs), mortality rates (ASMRs), and DALY rates were extracted for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Annual percent change (APC) was calculated using Joinpoint regression. Risk factor attribution was analyzed using comparative risk assessment methodology. Poisson regression models examined sex differences.
Results:
The pooled annual stroke incidence in Saudi Arabia was 29 per 100,000 population (95% CI: 15–47). Ischemic stroke predominated, comprising 79–87% of cases. Age-standardized DALYs showed significant yearly decreases of 9.28 per 100,000 (95% CI: 6.31–12.26, p < 0.001). The age-standardized death rate in the Middle East and North Africa (MENA) region was 87.7 per 100,000 [95% uncertainty interval (UI): 78.2–97.6] in 2019, representing a 27.8% regional decrease from 1990. Mean age at first stroke in Saudi Arabia was 63 years—six years younger than Western populations. Hypertension (57.7%), diabetes mellitus (49.4%), and obesity (42.0%) were the major modifiable risk factors. Intravenous thrombolysis utilization remained critically low at 1–3.6%.
Conclusions:
Despite declining mortality and DALYs, Saudi Arabia faces a substantial stroke burden characterized by a younger onset age and significant treatment gaps. Achieving Vision 2030 health targets requires accelerated primary prevention addressing metabolic risk factors and expansion of acute stroke treatment capacity nationwide.
Aim:
Stroke represents a leading cause of mortality and disability globally, yet comprehensive epidemiological analyses for Saudi Arabia remain limited. This study aimed to analyze temporal trends in stroke incidence, mortality, and disability-adjusted life years (DALYs) in Saudi Arabia from 1990 to 2021, examine stroke subtype distributions and risk factor attributions, and compare findings with regional and international benchmarks.
Methods:
We conducted a comprehensive analysis of the Global Burden of Disease (GBD) 2021 study data for Saudi Arabia, supplemented by systematic review findings and hospital-based registry data. Age-standardized incidence rates (ASIRs), mortality rates (ASMRs), and DALY rates were extracted for ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. Annual percent change (APC) was calculated using Joinpoint regression. Risk factor attribution was analyzed using comparative risk assessment methodology. Poisson regression models examined sex differences.
Results:
The pooled annual stroke incidence in Saudi Arabia was 29 per 100,000 population (95% CI: 15–47). Ischemic stroke predominated, comprising 79–87% of cases. Age-standardized DALYs showed significant yearly decreases of 9.28 per 100,000 (95% CI: 6.31–12.26, p < 0.001). The age-standardized death rate in the Middle East and North Africa (MENA) region was 87.7 per 100,000 [95% uncertainty interval (UI): 78.2–97.6] in 2019, representing a 27.8% regional decrease from 1990. Mean age at first stroke in Saudi Arabia was 63 years—six years younger than Western populations. Hypertension (57.7%), diabetes mellitus (49.4%), and obesity (42.0%) were the major modifiable risk factors. Intravenous thrombolysis utilization remained critically low at 1–3.6%.
Conclusions:
Despite declining mortality and DALYs, Saudi Arabia faces a substantial stroke burden characterized by a younger onset age and significant treatment gaps. Achieving Vision 2030 health targets requires accelerated primary prevention addressing metabolic risk factors and expansion of acute stroke treatment capacity nationwide.
DOI: https://doi.org/10.37349/en.2026.1006135
This article belongs to the special issue The Science of Ischemic Stroke
Major depressive disorder (MDD) is increasingly understood as a multifactorial psychiatric disorder involving interacting neural, immune, metabolic, and microbial processes. Within this framework, the microbiota–gut–brain axis and mitochondrial bioenergetics have emerged as potentially intersecting contributors to depressive symptomatology. Preclinical studies suggest that microbial metabolites—especially short-chain fatty acids (SCFAs)—can influence oxidative phosphorylation, redox balance, neuroinflammation, and synaptic plasticity, whereas inflammatory signals such as lipopolysaccharide may disrupt mitochondrial dynamics. However, the strength of evidence is uneven: mechanistic support is strongest in cell and animal models, whereas human data remain heterogeneous and largely associative. This narrative review critically synthesizes current evidence on microbiota–mitochondria crosstalk in MDD, distinguishing established findings from emerging hypotheses. It also examines recent psychobiotic trials, metabolomic and biomarker studies, and microglia–mitochondria mechanisms, and discusses the translational limitations that currently constrain clinical application. Overall, this axis represents a plausible and clinically relevant framework for hypothesis generation and adjunctive intervention development, but it should not yet be regarded as a fully validated causal pathway or stand-alone therapeutic target in MDD.
Major depressive disorder (MDD) is increasingly understood as a multifactorial psychiatric disorder involving interacting neural, immune, metabolic, and microbial processes. Within this framework, the microbiota–gut–brain axis and mitochondrial bioenergetics have emerged as potentially intersecting contributors to depressive symptomatology. Preclinical studies suggest that microbial metabolites—especially short-chain fatty acids (SCFAs)—can influence oxidative phosphorylation, redox balance, neuroinflammation, and synaptic plasticity, whereas inflammatory signals such as lipopolysaccharide may disrupt mitochondrial dynamics. However, the strength of evidence is uneven: mechanistic support is strongest in cell and animal models, whereas human data remain heterogeneous and largely associative. This narrative review critically synthesizes current evidence on microbiota–mitochondria crosstalk in MDD, distinguishing established findings from emerging hypotheses. It also examines recent psychobiotic trials, metabolomic and biomarker studies, and microglia–mitochondria mechanisms, and discusses the translational limitations that currently constrain clinical application. Overall, this axis represents a plausible and clinically relevant framework for hypothesis generation and adjunctive intervention development, but it should not yet be regarded as a fully validated causal pathway or stand-alone therapeutic target in MDD.
DOI: https://doi.org/10.37349/en.2026.1006133
This article belongs to the special issue Depression: From Pathophysiology to Treatment Innovation
There is a growing appreciation of the role of mitochondria in determining the interactions of CNS astrocytes, microglia, and neurons. The influence of circadian and systemic processes in regulating these interactions is relatively underexplored. Recent work has indicated the importance of night-time dampening and resetting in the pathoetiology of a diverse array of aging-associated medical conditions, including neurodegenerative disorders. The 10-fold decrease in pineal melatonin at night between childhood and the 9th decade of life is a major determinant of how aging associates with neurodegenerative disorders, cardiovascular disorders, and a wide range of tumors. It is proposed that the beneficial effects of pineal melatonin are mediated via its upregulation of the mitochondria-derived peptides (MDPs), including humanin. Although potentially induced in all mitochondria-containing cells, humanin is primarily produced in the CNS by astrocytes. The capacity of pineal melatonin to increase astrocyte humanin leads to the induction of the local melatonergic pathway in microglia to shift microglia from a pro-inflammatory M1-like to prophagocytic M2-like phenotype. In neurons, astrocyte-derived humanin optimizes mitochondrial function and decreases oxidant production to increase function and survival, possibly also involving mitochondrial melatonergic pathway upregulation. Concurrent effects of pineal melatonin in decreasing gut dysbiosis/permeability and stimulating oxytocin to activate the vagal nerve contribute to more optimized dampening and resetting that influences CNS interactions of glia and neurons. Overall, the conceptualizations of how astrocyte, microglial, and neuronal mitochondria interact require integration with wider circadian and systemic processes. A plethora of novel research implications are highlighted.
There is a growing appreciation of the role of mitochondria in determining the interactions of CNS astrocytes, microglia, and neurons. The influence of circadian and systemic processes in regulating these interactions is relatively underexplored. Recent work has indicated the importance of night-time dampening and resetting in the pathoetiology of a diverse array of aging-associated medical conditions, including neurodegenerative disorders. The 10-fold decrease in pineal melatonin at night between childhood and the 9th decade of life is a major determinant of how aging associates with neurodegenerative disorders, cardiovascular disorders, and a wide range of tumors. It is proposed that the beneficial effects of pineal melatonin are mediated via its upregulation of the mitochondria-derived peptides (MDPs), including humanin. Although potentially induced in all mitochondria-containing cells, humanin is primarily produced in the CNS by astrocytes. The capacity of pineal melatonin to increase astrocyte humanin leads to the induction of the local melatonergic pathway in microglia to shift microglia from a pro-inflammatory M1-like to prophagocytic M2-like phenotype. In neurons, astrocyte-derived humanin optimizes mitochondrial function and decreases oxidant production to increase function and survival, possibly also involving mitochondrial melatonergic pathway upregulation. Concurrent effects of pineal melatonin in decreasing gut dysbiosis/permeability and stimulating oxytocin to activate the vagal nerve contribute to more optimized dampening and resetting that influences CNS interactions of glia and neurons. Overall, the conceptualizations of how astrocyte, microglial, and neuronal mitochondria interact require integration with wider circadian and systemic processes. A plethora of novel research implications are highlighted.
DOI: https://doi.org/10.37349/en.2026.1006132
