CNS & Neurological Disorders - Drug Targets - Online First

Tobacco consumption is a worldwide issue that has significant health repercussions. Each year, related diseases result in an expenditure of billions of dollars in healthcare costs and diminished productivity. People are becoming more conscious of the fact that quitting smoking at any age can prolong life and lessen many of the negative consequences of smoking. While there are currently some treatment options available, there is still a substantial demand for novel and efficient pharmacotherapies to assist smokers in achieving and sustaining long-term sobriety. The symptoms of nicotine withdrawal are a significant obstacle to cessation and must be alleviated to prevent early recurrence. This article has discussed the neurotransmitters that are responsible for nicotine reward and the anatomical structures implicated in nicotine withdrawal. A simple hypothesis regarding tobacco addiction posits that nicotine is the primary addictive constituent of tobacco. Anxiety, depression, and stress have intricate effects on every facet of nicotine dependency, including the withdrawal experience. Smokers commonly utilize smoking as a means to reduce tension and anxiety, as it is believed to have a relaxing effect. This increasing knowledge offers a detailed understanding of the mechanisms behind existing and future smoking cessation treatments. Therefore, nicotine withdrawal is a significant factor influencing continued nicotine product use and contributes to unsuccessful cessation attempts. In conclusion, nicotine withdrawal may lead to cognitive changes and attention disturbances in the short term and enhance exercise-related physical abilities in the long term.

With a prevalence of almost one in eight people, psychiatric disorders are increasing at an alarming rate due to changes in lifestyle, stress, and dietary habits. Current diagnostic and treatment strategies for psychiatric disorders remain suboptimal and ineffective. Nanomedicine offers a transformative solution by overcoming critical barriers such as the blood-brain barrier, poor drug solubility, low bioavailability, and systemic side effects. Various nanocarriers like polymeric nanoparticles, dendrimers, liposomes, solid lipid nanoparticles, and inorganic nanomaterials demonstrate enhanced brain targeting, controlled drug release, improved therapeutic efficacy, and minimize systemic side effects across a range of psychiatric conditions. Nanomedicine applications span various psychiatric conditions, including depression, anxiety, schizophrenia, and autism, offering innovative solutions like intranasal drug delivery and ligand-targeted delivery systems. These systems exhibit promise in bypassing the blood-brain barrier and achieving site-specific drug delivery. This review highlights the increasing burden of psychiatric disorders, the limitations of current treatments, and the promise of nanomedicine in overcoming drug delivery challenges. It emphasizes how nanotechnology can enhance the pharmacokinetics and pharmacodynamics of psychotropic drugs, enable targeted and synergistic therapies, reduce side effects, and ultimately advance more personalized and effective psychiatric care.

Motor neuron disorders (MNDs), including ALS, are deadly neurodegenerative conditions that cause progressive motor neuron degeneration. With neuroprotection and the potential for neuron regeneration employing MSCs, ESCs, iPSCs, and NSCs, stem cell treatment presents a viable alternative to current medicines, which only control a limited number of symptoms. Following PRISMA criteria, this narrative review methodically screened 1248 records from the Cochrane, Web of Science, PubMed, and Scopus databases. Following a thorough screening process, 22 studies, including preclinical models and 19 clinical trials, were analysed to assess the therapeutic mechanisms, safety, and efficacy of stem cell therapies for MNDs. Mesenchymal stem cell (MSC) therapy has shown a promising safety profile and possible therapeutic efficacy in ALS, with no substantial transplant-related toxicity noted. ALS functional rating scale-revised (ALSFRS-R) scores and forced vital capacity (FVC) assessments from clinical trials, such as those evaluating autologous bone marrow-derived MSCs, demonstrated stabilisation in ALS development. Studies have also emphasised as to how immunomodulation and neurotrophic factors play a part in MSC-based therapies. Recent data indicate that repeated intrathecal MSC injection could extend the duration of therapeutic advantages. Clinical trials have shown safety and early efficacy signals for motor neurons produced from embryonic stem cells (ESCs), especially using AstroRx^®. This suggests that ESCs could be a viable option for regenerative medicine. Nonetheless, issues, like host integration and differentiation optimisation, still exist. Although clinical translation is still in its early stages, induced pluripotent stem cells (iPSCs) and their derivatives provide disease modelling and patient-specific therapeutic applications. Stem cell therapy holds promise for treating MND, with MSCs leading the way in current trials. It is necessary to enhance ESC- and iPSC-based techniques to tackle integration issues. To ensure long-term safety and efficacy, therapies must be developed using standardised protocols, patient stratification, optimised delivery, and large-scale studies.

Ischemic stroke occurs when reduced or blocked blood flow prevents oxygen and nutrients from reaching brain tissue, resulting in neurological deficits. It is a leading cause of disability and death worldwide, with varying degrees of brain injury, from tissue damage to neuronal death and functional impairments. While restoring blood flow is necessary, it can worsen damage through oxidative stress, pro-inflammatory cytokines, apoptosis, blood-brain barrier disruption, cerebral edema, and hemorrhagic transformation. Neuroprotection plays a crucial role in reducing ischemic damage, with therapies targeting antioxidant, anti-inflammatory, and anti-ferroptotic pathways being essential. Current treatments for ischemia remain insufficient, and there is a lack of comprehensive reviews on drug candidates targeting this condition. This review aims to address this gap by evaluating 271 potential drug candidates for cerebral ischemia. It presents an in-depth analysis of compounds with core structures such as triazole, piperazine, pyrrole, amide, pyridine, and oxadiazole, along with functional groups like hydroxyl, halogen, and alkyl groups. These compounds exhibit promising neuroprotective, antioxidant, anti-ferroptotic, and anti-inflammatory effects. The encouraging findings highlight the need for further research and optimization to develop more effective therapeutic agents, reduce mortality, and prevent permanent disabilities associated with ischemic brain injuries.

Autophagy is a catabolic process that helps maintain cellular homeostasis by degrading damaged proteins and organelles while recycling essential biomolecules. Neuropsychiatric disorders, such as schizophrenia, bipolar disorder, major depressive disorder, and substance use disorders, have been linked to autophagy dysregulation. In this manuscript, we review the complex role of autophagy in the neurobiology of these disorders, encompassing neuronal function, neurodevelopment, and neuroplasticity. The molecular mechanisms by which autophagy dysregulation contributes to the manifestation and progression of neuropsychiatric diseases, including those related to autophagy genes and pathways, are also discussed. Additionally, potential entry points for autophagy-targeted therapy in these disorders, such as modulating mTOR and combining autophagy modulators with existing treatments, are also explored. We also specifically examine the neuroprotective effects of lithium, a mood stabilizer, through its influence on autophagy pathways. Overall, understanding the intricate relationship between autophagy and neuropsychiatric disorders provides new avenues for developing new treatments for these devastating conditions.

Neurodegenerative and neurodevelopmental disorders represent a significant global health burden, characterized by progressive neuronal dysfunction and loss. Both diseases, despite their diverse etiologies and mechanisms, share a complex interplay of genetic, environmental, and biological factors. Neurodegenerative diseases are caused by multiple factors, including aging, mitochondrial dysfunction, oxidative stress, inflammation, genetic mutations, and protein misfolding. In contrast, neurodevelopmental disorders are primarily influenced by epigenetic alterations, neurotransmitter imbalances, early brain damage, environmental factors, and genetic variations. Despite extensive research, effective treatments remain unavailable due to the complexity of their pathologies and the biochemical pathways involved. A deep understanding of the complexities and individual differences associated with these disorders is crucial for developing effective treatments. In this background, this review provides a comprehensive overview of neurodegenerative and neurodevelopmental disorders, including their clinical symptoms, etiology, pathogenesis, underlying mechanisms, potential drug targets, reported drugs, advanced treatment options, and challenges in the drug discovery process. This comprehensive literature review was conducted using databases such as PubMed and Scopus, focusing on research published up to April 2025. By understanding the complexities of these disorders, researchers can develop novel therapeutic approaches, including potential drugs and advanced treatment methods, to mitigate their devastating impact.