CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 22, Issue 5, 2023

It is believed that degenerative conditions that give rise to neurological diseases may share an abnormal influx of Ca²⁺, mainly through glutamate receptors. Current research on the glutamatergic system indicates that the N-methyl-D-aspartate receptor (NMDAR) is not the only receptor permeable to Ca²⁺. Under certain conditions, α -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are able to rapidly and potently mediate a neurotoxic Ca²⁺ influx. AMPARs are encoded by four genes designated GluR 1-4. The presence of the edited GluA2 subunit makes the heteromeric AMPAR impermeable to Ca²⁺ (CI-AMPAR's). On the other hand, the lack of GluA2 or disruptions in its post-translational editing result in Ca²⁺-permeable AMPA receptors (CP-AMPARs). In addition to triggering behavioral changes, the increase in CP-AMPARs is documented in several neurodegenerative, neuroinflammatory and neurotoxic conditions, demonstrating that AMPAR changes may play a role in the emergence and evolution of pathological conditions of the central nervous system (CNS). Seeking to better understand how CP-AMPARs influence CNS neuropathology, and how it may serve as a pharmacological target for future molecules, in this article, we summarize and discuss studies investigating changes in the composition of AMPARs and their cellular and molecular effects, to improve the understanding of the therapeutic potential of the CP-AMPAR in neurodegenerative, neurotoxic and neuroinflammatory diseases.

Background: Medulloblastomas (MB) are the most common malignant brain tumors in the pediatric age. In 2021, WHO categorized medulloblastomas into two groups: molecularly defined and histologically defined medulloblastomas. Molecularly defined medulloblastomas are divided into WNTactivated medulloblastoma, SHH-activated and TP53-wildtype medulloblastoma, SHH-activated, and TP53-mutant and non-WNT/non-SHH medulloblastoma, which include Group 3 (MYC) and Group 4 (CDK6 and MYCN). In this paper, we will focus on molecularly defined medulloblastomas. Objective: This paper aims to review the literature in order to describe the molecular structure of the medulloblastoma groups and to emphasize the importance of genetic predictors in medulloblastoma that can be used in clinical practice, either as a prognostic tool or as a therapeutic target in the future. Results: Each molecular subtype of medulloblastoma presents a different prognosis, and the molecular subtype with the best prognosis is medulloblastoma-activated WNT. It has even been observed that a reduction in the intensity of the combined treatment does not modify the prognosis of the patients, resulting in even fewer adverse effects due to the treatment. On the other hand, it was observed that the subtypes with the worst prognosis are medulloblastomas with activated MYC and medulloblastomas with activated SHH and mutated TP53, due to their high capacity to metastasize or to their radio-resistance. However, a new target therapy has emerged that could help improve the prognosis in these patients. Conclusion: The deeper knowledge of the molecular pathways involved in the appearance and progression of medulloblastomas will allow us to offer a prognosis at the time of diagnosis and more specific treatments through the development of the targeted therapy.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent responsible for coronavirus disease (COVID-19), is an issue of global concern since March 2020. The respiratory manifestations of COVID-19 have widely been explained in the last couple of months of the pandemic. Initially, the virus was thought to be restricted to the pulmonary system; however, as time progressed and cases increased during the second wave of COVID-19, the virus affected other organs, including the nervous system. The neurological implication of SARS-CoV-2 infection is mounting, as substantiated by various reports, and in the majority of COVID-19 patients with neurological symptoms, the penetration of SARS-CoV-2 in the central nervous system (CNS) is likely. SARS-CoV-2 can enter the nervous system by exploiting the routes of olfactory mucosa, olfactory and sensory nerve endings, or endothelial and nerve tissues, thus crossing the neural-mucosal interface in the olfactory mucosa in the nose. Owing to multifactorial and complex pathogenic mechanisms, COVID-19 adds a large-scale risk to the entire nervous system. A thorough understanding of SARSCoV- 2 neurological damage is still vague; however, our comprehension of the virus is rapidly developing. The present comprehensive review will gain insights and provide neurological dimensions of COVID-19 and their associated anomalies. The review presents the entry routes of SARS-CoV-2 into the CNS to ascertain potential targets in the tissues owing to infection. We also discuss the molecular mechanisms involved, the array of clinical symptoms, and various nervous system diseases following the attack of SARS-CoV-2.

Autistic spectrum disorder (ASD) is a complicated developmental disease characterized by persistent difficulties in social interaction, speech and nonverbal communication, and restricted/ repetitive activities. Our goal is to deliver a step ahead awareness on neurodevelopment in ASD through early behavioral screenings, genetic testing, and detection of various environmental triggers. This would significantly reduce the tally of people with autistic characteristics. As of now, much work is to be done in understanding and treating ASD. Firstly, awareness campaigns must be organized and maintained so that ASD children can be identified and treated feasibly. Secondly, prenatal and prepregnancy environmental risk awareness, including advice against consanguineous marriages, information on optimum mother nutrition, and minimizing pollutants exposure, can be focused. Finally, the extension of genetic screening along with early postnatal monitoring of newborn feeding, nutrition, and eye contact will help in early therapy. People with ASD have strict dietary habits, but they are also more prone to gastrointestinal problems, including diarrhoea, constipation, and sometimes irritable bowel syndrome. Despite significant studies on the symptoms and possible causes of ASD, GI dysfunction is becoming a hot issue of discussion. Dietary strategies can partially help to alleviate both GI and behavioural issues due to the link between gut-microbiota and brain activity. Dietary treatments may be less expensive, easier to administer and have fewer adverse effects than pharmacological interventions. Hence, there is an increasing interest in autistic children's customized diets and supplements. Future studies should look at whether these diets are applicable to diverse people and whether they are practical in various circumstances (areas with fewer resources, lower socioeconomic areas, countries with different dietary restrictions, etc.). The dietary phytochemicals, including curcumin, resveratrol, naringenin, and sulforaphane, have a substantial role as neurotherapeutic agents. These agents can act as an antioxidant, immunomodulator, gut microbiota modulator and Nrf2 activator to provide benefits to ASD patients. Hence an urgent need is to create brain-targeted delivery methods for these dietary phytochemicals and to investigate their therapeutic value in ASD.

The autosomal recessive cerebellar ataxias (ARCAs) compose a clinically and genetically heterogeneous group of neurodegenerative diseases characterized by prominent cerebellar ataxia, dysmetria, dysarthria, and nystagmus that are inherited in an autosomal recessive fashion. The diagnosis of ARCAs is challenging because of their low prevalence, poor medical recognition, and heterogeneous clinical presentation with many overlapping features between entities. There currently exist no disease-modifying therapies for most ARCAs, and treatment is mainly symptomatic, aimed at prolonging independence and maintaining the quality of life. As knowledge of the common pathogenic pathways underlying several ARCAs grows, so do these pathways to target with new drugs. Chelation or enzyme replacement therapies are available for some specific ataxias caused by amenable metabolic alterations. A large number of drug trials are ongoing and aim to identify new therapeutic approaches to expand the options in our repertoire. Improved protocols of motor rehabilitation and noninvasive cerebellar stimulation have been shown to delay disease progression and maintain quality of life. Furthermore, recent progress in gene and molecular targeting therapies is rapidly expanding and holds promise for repairing defective genes. Neurotransplantation of grafted stem cells, which is still at the experimental preclinical stage, has opened new therapeutic strategies aimed at delaying cell degeneration and facilitating compensatory functions. This article is an overview of the current management and treatment strategies with an emphasis on promising perspectives for patients with ARCAs.

Epilepsy and migraine are chronic neurological disorders with shared clinical as well as pathophysiological mechanisms. Epileptic patients are at a higher risk of developing migraine compared to normal individuals and vice versa. Several genetic and environmental risk factors have been reported to be associated with the development of both diseases. Previous studies have already established standard genetic markers involved in various pathways implicated in the pathogenesis of both these comorbid conditions. In addition to genetic markers, epigenetic markers have also been found to be involved in the pathogenesis of epilepsy and migraine. Among the epigenetic markers, miRNAs have been explored at length and have emerged as significant players in regulating the expression of their target genes. miRNAs like miR-22, miR-34a, miR-155, miR-211, and Let-7b play a significant role in neuronal differentiation and seem to be associated with epilepsy and migraine as comorbid conditions. However, the exact shared mechanisms underlying the role of these miRNAs in these comorbid conditions are still unclear. The current review has been compiled with an aim to explore common microRNAs targeting the genes involved in shared molecular pathways leading to epilepsy and migraine as comorbid conditions. The new class of ncRNAs, i.e., tRNA transfer fragments, are also discussed. In addition, their role as potential biomarkers and therapeutic targets has also been evaluated. However, limitations exist, and based on the current literature available, only a few microRNAs seem to be involved in the pathogenesis of both these disorders.

The effects of a sufficient amount of vitamins and nutrients on the proper function of the nervous system have always been regarded by scientists. In recent years, many studies have been done on controlling or improving the symptoms of neurological and behavioral disorders created by changes in the level of vitamins and other nutrition, such as omega-3 and iron supplements. Autism spectrum disorder (ASD) is a neurodevelopmental disorder that disrupts individual communication, especially in social interactions. Its symptoms include anxiety, violence, depression, self-injury, trouble with social contact and pervasive, stereotyped, and repetitive behavior. ASD is most noticeable in early childhood. Attention Deficit Hyperactivity Disorder (ADHD) is a lasting pattern of inattention with or without hyperactivity that causes functional disruption in daily life. ADHD symptoms included; impulsivity, hyperactivity, inattention, restlessness, talkativeness, excessive fidgeting in situations such as sitting, meetings, lectures, or at the movies, boredom, inability to make decisions, and procrastination. The exact etiology of ADHD has not yet been found, but several observations have assumed the reduced function of the brain leads to deficits in motor planning and cognitive processing. It has been shown that Pro-inflammatory cytokines and oxidative stress biomarkers could be increased in both ASD and ADHD. Several studies have been done to illustrate if vitamins and other dietary supplements are effective in treating and preventing ASD and ADHD. In this review, we aim to evaluate the effects of vitamins and other dietary supplements (e.g., melatonin, zinc supplements, magnesium supplements) on ASD and ADHD.

Alzheimer’s disease (AD) is a neurodegenerative disease that involves several impaired neuronal pathways. Modulating the amyloid-beta (β-amyloid) system is being tested to treat AD. Amyloid-beta neurotoxicity is associated with neuroinflammation and plaque formation, further progressing to AD. Protecting neurons from β-amyloid neurotoxicity could be an efficient strategy for the treatment of AD. Thymoquinone (TQ) is an active ingredient in Nigella sativa (NS) and has shown effective therapeutic properties in AD models. TQ was able to attenuate the behavioral dysfunctions in AD models. Moreover, TQ could attenuate the neuroinflammation properties in animals with AD. In addition, studies have shown that TQ could modulate β -amyloid neurotoxicity, an effect associated with improved AD behavioral symptoms. In this review, we highlighted the therapeutic effects of TQ on the progression of AD through modulating β-amyloid neurotoxicity and neuro-inflammatory cytokine levels. Other phenolic compounds also present in NS improved behavioral and neuronal impairments in AD models, supporting TQ’s anti-Alzhiemer’s efficacy.

Objective: To evaluate the safety and effectiveness of levetiracetam and phenytoin by evaluating the events of seizure termination and recurrence in children. Methods: We used the internet databases PubMed, Embase, and Google Scholar to conduct a literature search for the appropriate studies. A meta-analysis was performed to calculate the odds ratio using fixed and random-effects models. Results: We identified 15 studies that were eligible for the meta-analysis. The incidence of seizure termination within 24 h was 76.9% for levetiracetam and 70.5% for phenytoin. Levetiracetam had a higher number of seizure termination events than phenytoin (P = 0.005, I² = 66%). The incidence of seizure recurrence within 24 h was 10% for levetiracetam and 15.6% for phenytoin. Phenytoin had a significantly higher number of seizure recurrence events than levetiracetam (P = 0.00007, I² = 21%). Conclusion: The efficacy and safety of levetiracetam are superior to that of phenytoin in children with status epilepticus. Large Randomized Controlled Trial studies are needed to confirm the result in children.

Background: Vitamin D has been extensively studied for its role in immune modulation, especially in the process of tolerance induction. The loss of tolerance towards self-antigens is the basis of several autoimmune disorders; this seems to be related to lower levels of Vitamin D. A neurological autoimmune disorder due to the loss of tolerance to compounds at the neuromuscular junction is known as Myasthenia Gravis (MG). Objective: To assess the possible correlation between altered Vitamin D levels and MG. Methods: In this systematic review, all recruited studies compared Vitamin D levels in MG patients and healthy controls. Five studies fulfilled the selection criteria and were included in the quantitative synthesis. The meta-analysis involved data of a total population size of 450 individuals, equally divided into 219 cases and 231 controls. Results: The results showed a statistically significant mean difference between cases and controls. The overall mean Vitamin D levels in MG patients were 4.69 ng/ml lower than control levels (95% CI -6.17; -3.22); by applying a random-effects model, this mean difference was estimated at -3.79 (95% CI -7.24; -0.33), after exclusion of data source of heterogeneity and through applying a fixed-effect model, resulted in a mean difference -5.39 (95% CI -6.91; -3.88). The p-value was lower than 0.05. Conclusion: There are statistically significant lower levels of Vitamin D in MG patients, so routine checking and possible correction should be advised in MG patients based on the current data.

Background: Twenty million Americans suffer from peripheral nerve injury (PNI) and approximately $150 billion is spent annually in the United States for the treatment of nerve injuries. Moreover, 50,000 cases of PNI repairs are performed annually in the United States, with even less than 42% experiencing satisfactory sensory recovery. Available therapies control painful symptoms but do not treat axonal degeneration or neuronal cell death. Peripheral nerve fibrosis (PNF) associated with chronic inflammation, perineural adhesions, and scarring is often reported in patients with nerve injury. Unfortunately, post-surgical adhesions and fibrosis often lead to aberrated wound healing and impairment of nerve functions. Various treatment strategies have been attempted, including the use of grafts and biomaterials; however, few appear promising. Objective: L-Alanyl-L-Glutamine (L-Ala-L-Gln) was reported to protect the lung from sepsisinduced injury and play an immunomodulatory role in stress and fibrosis. This study aimed to examine the potential anti-fibrotic effects of L-Ala-L-Gln in an in vitro model of neural fibrosis. Methods: Primary fibroblasts isolated from rat sciatic nerve were exposed to chronic (48 h) and episodic (2 h) hypoxic conditions. Cultures were then treated for 48 h with various concentrations of L-Ala-L-Gln (0, 1, 10, and 100 mM). The expression of hypoxic and pro-fibrotic markers in the different culture conditions was assessed by immunocytochemistry and western blot analyses. Quantitative phosphor-proteomic profiling was performed to investigate mechanistically the impact of L-Ala- L-Gln on collagen biosynthesis and hypoxia-driven tissue fibrosis in vitro. Results: In protein expression assays, L-Ala-L-Gln significantly reduced markers related to the cellular response to hypoxia, in particular HIF-1 signaling. L-Ala-L-Gln also significantly reduced the expression of pro-fibrotic and cell-adhesion-inducing factors. Phospho-proteomic data indicated that L-Ala-L-Gln modulates several pro-fibrotic factors and associated pathways. Conclusion: Altogether, our data demonstrate that L-Ala-L-Gln efficiently suppresses hypoxiamediated fibrotic processes at different concentrations in rat primary fibroblasts. Thus, L-Ala-L-Gln presents a high potential therapeutic value as an antifibrotic pharmaceutical agent for the treatment of neural fibrosis.

Background: Epilepsy is a common neurological disorder affecting more than 70 million people worldwide. Despite numerous efforts on new antiepileptic drugs, approximately one-third of epilepsy patients suffer from uncontrolled seizures. It leads to serious psychosocial consequences, cognitive problems, and decreased quality of life. Objective: Our previous studies have shown that N. incisum root extract (NRE) can improve cognitive dysfunction in Alzheimer's disease (AD) mice. In addition, our research shows that AD and epilepsy have pathological mechanisms overlapping. Therefore, we tried to investigate whether NRE can ameliorate the seizures of epileptic mice in this study. Methods: NRE-treated mice group was given an oral administration with 1 g/kg/d for 7 days. On the 8th day, mice were exposed to PTZ (i.p. injection) to induce epilepsy. Then the cognitive tests of mice in the water maze were carried out, and the biochemical indexes and pathological tests were carried out after the mice were sacrificed. Results: SOD level in the NRE group was significantly higher than that in the PTZ group, while MDA, TNF-α, and IL-1β levels were decreased. The cognitive ability of NRE-treated mice was significantly improved compared with the PTZ group. Immunohistochemistry (IHC) results showed that the activation of microglia and astrocytes in the hippocampus and cortex of NRE mice were inhibited. Conclusion: This study suggests that NRE can alleviate epilepsy and improve cognitive function in mice with epilepsy, and its mechanism may be through reducing inflammation and enhancing antioxidant defense.