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.

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.

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.

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.

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.

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.