Current Neuropharmacology - Volume 22, Issue 14, 2024

The human central nervous system (CNS) has a limited capacity for regeneration and repair, as many other organs do. Partly as a result, neurological diseases are the leading cause of medical burden globally. Most neurological disorders cannot be cured, and primary treatments focus on managing their symptoms and slowing down their progression. Cell therapy for neurological disorders offers several therapeutic potentials and provides hope for many patients. Here we provide a general overview of cell therapy in neurological disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Wilson’s disease (WD), stroke and traumatic brain injury (TBI), involving many forms of stem cells, including embryonic stem cells and induced pluripotent stem cells. We also address the current concerns and perspectives for the future. Most studies for cell therapy in neurological diseases are in the pre-clinical stage, and there is still a great need for further research to translate neural replacement and regenerative therapies into clinical settings.

Extrapyramidal hyperkinetic movement disorders comprise a broad range of phenotypic phenomena, including chorea, dystonia, and tics. Treatment is generally challenging and individualized, given the overlapping phenomenology, limited evidence regarding efficacy, and concerns regarding the tolerability and safety of most treatments. Over the past decade, the treatment has become even more intricate due to advancements in the field of deep brain stimulation as well as optimized dopamine-depleting agents. Here, we review the current evidence for treatment modalities of extrapyramidal hyperkinetic movement disorders and provide a comprehensive and practical overview to aid the choice of therapy. Mechanism of action and practical intricacies of each treatment modality are discussed, focusing on dosing and adverse effect management. Finally, future therapeutic developments are also discussed.

Traumatic brain injury (TBI) is a significant global health problem, leading to high rates of mortality and disability. It occurs when an external force damages the brain, causing immediate harm and triggering further pathological processes that exacerbate the condition. Despite its widespread impact, the underlying mechanisms of TBI remain poorly understood, and there are no specific pharmacological treatments available. This creates an urgent need for new, effective neuroprotective drugs and strategies tailored to the diverse needs of TBI patients. In the realm of gene expression regulation, chromatin acetylation plays a pivotal role. This process is controlled by two classes of enzymes: histone acetyltransferase (HAT) and histone deacetylase (HDAC). These enzymes modify lysine residues on histone proteins, thereby determining the acetylation status of chromatin. HDACs, in particular, are involved in the epigenetic regulation of gene expression in TBI. Recent research has highlighted the potential of HDAC inhibitors (HDACIs) as promising neuroprotective agents. These compounds have shown encouraging results in animal models of various neurodegenerative diseases. HDACIs offer multiple avenues for TBI management: they mitigate the neuroinflammatory response, alleviate oxidative stress, inhibit neuronal apoptosis, and promote neurogenesis and axonal regeneration. Additionally, they reduce glial activation, which is associated with TBI-induced neuroinflammation. This review aims to provide a comprehensive overview of the roles and mechanisms of HDACs in TBI and to evaluate the therapeutic potential of HDACIs. By summarizing current knowledge and emphasizing the neuroregenerative capabilities of HDACIs, this review seeks to advance TBI management and contribute to the development of targeted treatments.

Alzheimer's disease (AD) is the most prevalent type of dementia, but its etiopathogenesis is not yet fully understood. Recent preclinical studies and clinical evidence indicate that changes in the gut microbiome could potentially play a role in the accumulation of amyloid beta. However, the relationship between gut dysbiosis and AD is still elusive. In this review, the potential impact of the gut microbiome on AD development and progression is discussed. Pre-clinical and clinical literature exploring changes in gut microbiome composition is assessed, which can contribute to AD pathology including increased amyloid beta deposition and cognitive impairment. The gut-brain axis and the potential involvement of metabolites produced by the gut microbiome in AD are also highlighted. Furthermore, the potential of antibiotics, prebiotics, probiotics, fecal microbiota transplantation, and dietary interventions as complementary therapies for the management of AD is summarized. This review provides valuable insights into potential therapeutic strategies to modulate the gut microbiome in AD.

Cerebral Edema (CE) is the final common pathway of brain death. In severe neurological disease, neuronal cell damage first contributes to tissue edema, and then Increased Intracranial Pressure (ICP) occurs, which results in diminishing cerebral perfusion pressure. In turn, anoxic brain injury brought on by decreased cerebral perfusion pressure eventually results in neuronal cell impairment, creating a vicious cycle. Traditionally, CE is understood to be tightly linked to elevated ICP, which ultimately generates cerebral hernia and is therefore regarded as a risk factor for mortality. Intracranial hypertension and brain edema are two serious neurological disorders that are commonly treated with mannitol. However, mannitol usage should be monitored since inappropriate utilization of the substance could conversely have negative effects on CE patients. CE is thought to be related to blood-brain barrier dysfunction. Nonetheless, a fluid clearance mechanism called the glial-lymphatic or glymphatic system was updated. This pathway facilitates the transport of cerebrospinal fluid (CSF) into the brain along arterial perivascular spaces and later into the brain interstitium. After removing solutes from the neuropil into meningeal and cervical lymphatic drainage arteries, the route then directs flows into the venous perivascular and perineuronal regions. Remarkably, the dual function of the glymphatic system was observed to protect the brain from further exacerbated damage. From our point of view, future studies ought to concentrate on the management of CE based on numerous targets of the updated glymphatic system. Further clinical trials are encouraged to apply these agents to the clinic as soon as possible.

Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder that greatly affects the health and life quality of the elderly population. Existing drugs mainly alleviate symptoms but fail to halt disease progression, underscoring the urgent need for the development of novel drugs. Based on the neuroprotective effects of flavonoid quercetin in AD, this study was designed to identify potential AD-related targets for quercetin and perform in silico prediction of promising analogs for the treatment of AD. Database mining suggested death-associated protein kinase 1 (DAPK1) as the most promising AD-related target for quercetin among seven protein candidates. To achieve better biological effects for the treatment of AD, we devised a series of quercetin analogs as ligands for DAPK1, and molecular docking analyses, absorption, distribution, metabolism, and excretion (ADME) predictions, as well as molecular dynamics (MD) simulations, were performed. The energy for drug-protein interaction was predicted and ranked. As a result, quercetin-A1a and quercetin-A1a1 out of 19 quercetin analogs exhibited the lowest interaction energy for binding to DAPK1 than quercetin, and they had similar dynamics performance with quercetin. In addition, quercetin-A1a and quercetin-A1a1 were predicted to have better water solubility. Thus, quercetin-A1a and quercetin-A1a1 could be promising agents for the treatment of AD. Our findings paved the way for further experimental studies and the development of novel drugs.

Stroke is a neurological disorder with high disability and mortality rates. Almost 80% of stroke cases are ischemic stroke, and the remaining are hemorrhagic stroke. The only approved treatment for ischemic stroke is thrombolysis and/or thrombectomy. However, these treatments cannot sufficiently relieve the disease outcome, and many patients remain disabled even after effective thrombolysis. Therefore, rehabilitative therapies are necessary to induce remodeling in the brain. Currently, stem cell transplantation, especially via the use of induced pluripotent stem cells (iPSCs), is considered a promising alternative therapy for stimulating neurogenesis and brain remodeling. iPSCs are generated from somatic cells by specific transcription factors. The biological functions of iPSCs are similar to those of embryonic stem cells (ESCs), including immunomodulation, reduced cerebral blood flow, cerebral edema, and autophagy. Although iPSC therapy plays a promising role in both hemorrhagic and ischemic stroke, its application is associated with certain limitations. Tumor formation, immune rejection, stem cell survival, and migration are some concerns associated with stem cell therapy. Therefore, cell-free therapy as an alternative method can overcome these limitations. This study reviews the therapeutic application of iPSCs in stroke models and the underlying mechanisms and constraints of these cells. Moreover, cell-free therapy using exosomes, apoptotic bodies, and microvesicles as alternative treatments is discussed.

Psychiatric disorders are complex, multifactorial illnesses. It is challenging for us to understand the underlying mechanism of psychiatric disorders. In recent years, the morbidity of psychiatric disorders has increased yearly, causing huge economic losses to the society. Although some progress, such as psychotherapy drugs and electroconvulsive therapy, has been made in the treatment of psychiatric disorders, including depression, anxiety, bipolar disorder, obsessive-compulsive and autism spectrum disorders, antidepressants and psychotropic drugs have the characteristics of negative effects and high rate of relapse. Therefore, researchers continue to seek suitable interventions. cAMP response element binding protein (CREB) belongs to a protein family and is widely distributed in the majority of brain cells that function as a transcription factor. It has been demonstrated that CREB plays an important role in neurogenesis, synaptic plasticity, and neuronal growth. This review provides a 10-year update of the 2013 systematic review on the multidimensional roles of CREB-mediated transcriptional signaling in psychiatric disorders. We also summarize the classification of psychiatric disorders and elucidate the involvement of CREB and related downstream signalling pathways in psychiatric disorders. Importantly, we analyse the CREB-related signal pathways involving antidepressants and antipsychotics to relieve the pathological process of psychiatric disorders. This review emphasizes that CREB signalling may have a vast potential to treat psychiatric disorders like depression. Furthermore, it would be helpful for the development of potential medicine to make up for the imperfection of current antidepressants and antipsychotics.

There is much debate about continuing antipsychotic medication in patients who need it when they become pregnant because benefits must be weighed against potential teratogenic and malformation effects related to antipsychotics themselves. To address this, we conducted a systematic review on the PubMed, PsycINFO and CINHAL databases and the ClinicalTrials.gov register using the following strategy: (toxicity OR teratogenicity OR malformation* OR “birth defect*” OR “congenital abnormality” OR “congenital abnormalities” OR “brain changes” OR “behavioral abnormalities” OR “behavioral abnormalities”) AND antipsychotic* AND (pregnancy OR pregnant OR lactation OR delivery OR prenatal OR perinatal OR post-natal OR puerperium) on September 27, 2023. We found 38 studies to be eligible. The oldest was published in 1976, while most articles were recent. Most studies concluded that the antipsychotics, especially the second-generation antipsychotics, were devoid of teratogenic potential, while few studies were inconclusive and recommended replication. Most authoritative articles were from the Boston area, where large databases were implemented to study the malformation potential of psychiatric drugs. Other reliable databases are from Northern European registers. Overall conclusions are that antipsychotics are no more related to malformations than the disorders themselves; most studies recommend that there are no reasons to discontinue antipsychotic medications in pregnancy.