CNS & Neurological Disorders - Drug Targets - Online First

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.

Neurological disorders are complex conditions characterized by impairment of the nervous system, affecting motor, cognitive, and sensory functions. Current treatments meet substantial obstacles, primarily due to the difficulty of transporting drugs across the blood-brain barrier and ineffective therapy for nerve regeneration. Emerging technologies, such as electrospinning, offer innovative solutions to overcome these challenges. The study explores the potential of electrospun food fibers in managing and treating neurological disorders, concentrating on their role in drug delivery and nerve tissue regeneration. Electrospinning allows for the generation of nanofibers from diverse natural and synthetic polymers that imitate the extracellular matrix and stimulate brain healing. These fibers may be loaded with therapeutic drugs, permitting controlled, localized drug release while limiting systemic toxicity. For instance, electrospun fibers loaded with neuroprotective drugs, such as donepezil and levodopa, have exhibited better drug stability, enhanced bioavailability, and prolonged therapeutic efficacy in treating syndromes such as Alzheimer’s and Parkinson’s diseases. Furthermore, the biodegradable and biocompatible nature of food-based polymers like chitosan, cellulose, and zein makes them great candidates for medicinal applications, minimizing the risk of inflammation and unfavorable immunological reactions. In conclusion, electrospun food fibers show tremendous promise in resolving the issues of drug delivery and nerve regeneration in neurological illnesses. Their capacity to boost therapeutic results via targeted and regulated drug release makes them a possible alternative to established treatment procedures, bringing renewed hope to patients suffering from neurodegenerative disorders.

Several organosulfur compounds exhibit anti-Parkinson's disease (PD) activities. PD is a progressive and chronic neurodegenerative condition that causes motor and non-motor symptoms that severely reduce quality of life. A selective loss of dopaminergic neurons in the substantia nigra, in addition to several neuropathological mechanisms, has been implicated in PD. The present therapeutic techniques are mostly focused on providing symptomatic relief and frequently have significant side effects, which underscores the pressing need for innovative medicines that address the underlying causes of disease. Several organosulfur compounds, both synthesized and naturally occurring analogues, have gained attention as potential anti-PD molecules because of their wide range of biological activities, which include anti-inflammatory, neuroprotective, and antioxidant capabilities. Several organosulfur compounds have been shown to have potential neuroprotective benefits in preclinical research on PD. Their ability to attenuate neuroinflammation, oxidative stress, apoptosis, and mitochondrial dysfunction, which are central to PD pathogenesis via modulation of cellular pathways and endogenous antioxidant defenses, provides multifaceted approaches to neuroprotection in PD. Thus, the current review provides the state of the art on the potential therapeutic effects of organosulfur compounds in PD. The natural and synthetic sources of anti-PD organosulfur compounds, including their physical properties, chemical properties, structure-activity relationship (SAR), and therapeutic effects in PD, were discussed. The challenges and future directions of organosulfur compounds as potential anti-PD drugs and their clinical trial prospects were also highlighted. This is aimed at paving the way for the development of more effective and sustainable treatment strategies for PD.

Persistent swelling in the brain, internal tau bundles, and external Amyloid-Beta (Aβ) deposits are characteristics of Alzheimer's Disease (AD), an ongoing neurodegenerative illness. Microglia are the main immune cells in the CNS (Central Nervous System). They keep the brain stable by keeping an eye on the immune system and removing apoptotic cells and protein clusters through a process called phagocytosis. However, in AD, microglia exhibit dysregulated phagocytic activity, resulting in either insufficient Aβ clearance or exacerbated inflammatory responses, both of which contribute to neurodegeneration. This review examines key molecular pathways, such as those mediated by TREM2 (Triggering Receptor Expressed on Myeloid cells), APOE (Apolipoprotein E), and CD33 (Cluster of Differentiation), that govern microglial activation and influence their neuroprotective or neurotoxic functions. We further explore therapeutic strategies to modulate microglial phagocytosis, pharmacological agents (such as minocycline, pioglitazone, rifampicin, etc.), some natural agents, gene-editing tools, and nanomedicine, which aim to optimise microglial response and reduce the neuroinflammatory burden in AD. Despite promising advances, challenges persist in achieving targeted, effective modulation of microglial function due to microglial heterogeneity, limited model fidelity, and potential off-target effects. This review underscores the importance of refining microglia-targeted interventions and developing combinatory approaches that enhance microglial homeostasis to mitigate AD pathology and progression.

The normal cellular prion protein (PrP^C) can misfold into an infectious and pathogenic form (PrP^Sc) to produce prion diseases, also known as transmissible spongiform encephalopathies (TSEs), which are rare and deadly neurodegenerative conditions. The conversion of PrP^C to PrP^𝑆𝑐, which builds up as toxic aggregates in the central nervous system, is caused by sporadic, inherited, or acquired pathways. PrP^Sc-induced proteostasis failure, oxidative stress, neuronal toxicity, and progressive neurodegeneration are characteristics of pathogenesis. Due to their overlap with other neurodegenerative illnesses, prion diseases are still difficult to diagnose, even with breakthroughs in our knowledge of the molecular causes. Cerebrospinal fluid biomarkers, neuroimaging, EEG, and genetic testing are utilized in the diagnostic process. Methods like real-time quaking-induced conversion (RT-QuIC) provide high sensitivity. As there are currently no cures, the main goals of management are palliative care and symptom alleviation. Research is currently being conducted on experimental strategies that target PrP misfolding. These strategies include autophagy enhancers, monoclonal antibodies, antisense oligonucleotides, and small compounds. Artificial intelligence (AI) shows revolutionary promise by enhancing early diagnosis through biomarker analysis, neuroimaging interpretation, and EEG pattern identification. AI also improves clinical trial design, identifies tailored treatment approaches, and accelerates drug discovery. Furthermore, advancements in AI-based bioinformatics technologies have led to a better understanding of prion biology and strain diversity. The future holds promise for utilising cutting-edge treatment techniques, such as CRISPR and gene therapy, for targeted interventions, as well as combining AI with multimodal data to enhance diagnostic capabilities. There is optimism that the burden of prion disorders can be reduced, and the treatment of neurodegenerative illnesses can be improved through the integration of molecular research, novel treatments, and AI technology.

Alzheimer's disease (AD) is a typical neurodegenerative illness, and it is a main cause of dementia, affecting millions of older populations throughout the world. Although the exact causes of AD are still not clear, the disorder is known to be considered by the accumulation of amyloid plaques and tau tangles in the neuronal cells. Currently, available drugs such as cholinesterase inhibitors and NMDA antagonists can help manage symptoms but don’t address the underlying causes of the disease. New experimental treatments targeting amyloid and tau proteins show promise but are still in clinical trials. Recently, β-Amyloid has gained attention as an emerging target to develop new medications as it is strongly involved in the pathophysiology of AD. β-Amyloidpathies are directly or indirectly linked with multiple pathways, including GSK3β, insulin resistance, NMDA dysfunction, AMP-activated kinase, cholesterol mechanism, mitochondrial dysfunction, neuroinflammation, and SIRT1. However, several β-Amyloid targeting therapies employing various mechanisms have shown partial success in clinical trials, possibly due to a lack of understanding of the molecular link of this peptide with other pathways. Therefore, this paper has discussed the β-Amyloid molecular mechanisms involved in pathophysiological pathways to manage neuronal disorders and intracellular signal transduction effectively.

Parkinson’s disease is considered an advancing neurodegenerative disorder with unknown causes, and its association with some risk factors, including aging, family history, and exposure to chemicals, makes it the second most common occurring neurodegenerative disorder throughout the world with increasing prevalence. Parkinson’s disease is associated with slow movement, rigidity, tremors, imbalance, depression, anxiety, cognitive impairment, orthostasis, hyperhidrosis, sleep disorders, pain, and sensory disturbances. In recent decades, there has been a rise in research on the development of effective and potential therapies for the treatment of Parkinson’s disease. An important target for neuroprotection is Monoamine Oxidases (MAO), which hydrolyze neurotransmitters like dopamine and produce very reactive free radicals as a by-product. Aging and neurodegenerative illnesses cause overexpression in the brain, which exacerbates neuronal loss. The treatment of Parkinson's disease with MAO inhibitors has shown promising outcomes. Herein, we reported characteristic features of Parkinson’s disease, various treatment strategies, and the SAR of potential drugs that can be explored further as lead for the development of newer molecules with improved pharmacological profiles.

Alzheimer's Disease (AD) is a serious neurodegenerative condition that predominantly impacts the cholinergic neurons of the entorhinal cortex and hippocampal regions, playing a critical role in learning, navigation, and brain processing. This paper aims to discuss the three main hypotheses of Alzheimer's disease, focusing on neurotoxicity and neurodegeneration caused by mitochondrial dysfunction and ROS production, particularly analyzing the susceptibility differences between genders. Our comprehensive review focuses on significant findings from the past five years, particularly on Cholinesterase (ChE) and BACE-1 inhibitors. Researchers have conducted a detailed analysis of in vitro, in silico, and in vivo data, incorporating extensive Structure-Activity Relationship (SAR) studies. The reviewed papers have been sourced from platforms, such as Google Scholar, Semantic Scholar, and ClinicalTrials.gov, and have been selected based on their AChE and BACE-1 inhibitory activity and structural motif similarity. The review identifies the most effective compounds targeting ChE and BACE-1, highlighting acridine, dihydropyridine, and thiazole-coumarin hybrids for ChE inhibition, and oxadiazole, benzofuran, and dihydropyrimidinone for BACE-1 inhibition. This demonstrates a diverse array of potent heterocyclic hybrids. The review presents a varied compilation of scaffolds showing promise in treating Alzheimer's disease, highlighting the potential of specific compounds against ChE and BACE-1. Given the critical insights derived from our analysis, we posit that this compilation will substantially contribute to the ongoing efforts to combat neurodegeneration and prolong dementia, underscoring the importance of continuous research in this domain.