CNS & Neurological Disorders - Drug Targets - Volume 20, Issue 5, 2021

A letter to the editor to discuss several uses of brain magnetic resonance imaging (MRI) in the investigation of neurological manifestations of covid-19. Described several situations in which the MRI is needed. Brain MRI is an important diagnostic method in the covid-19 scenario, to investigate possible neurological complications of the disease.

Background: Over the past three decades, NMDA-receptor antagonists have been shown to be efficient drugs for treating pain, particularly pain resistant to conventional analgesics. Emphasis will be on the old-new drugs, ketamine and magnesium, and their combination as a novel approach for treating chronic pain. Methods: The MEDLINE database was searched via PubMed for articles that were published up to March 1, 2020, with the keywords ‘ketamine’, ‘magnesium’, and ‘pain’ (in the title/abstract). Results: Studies in animals, as well as humans, have shown that interactions of ketamine and magnesium can be additive, antagonistic, and synergistic. These discrepancies might be due to differences in magnesium and ketamine dosage, administration times, and the chronological order of drug administration. Different kinds of pain can also be the source of divergent results. Conclusion: This review explains why studies performed with a combination of ketamine and magnesium have given inconsistent results. Because of the lack of efficacy of drugs available for pain, ketamine and magnesium in combination provide a novel therapeutic approach that needs to be standardized with a suitable dosing regimen, including the chronological order of drug administration.

The gastrointestinal tract is a major organ of the body that absorbs nutrients, water, and electrolytes. At the same time, it is a tight barrier that resists the invasion of harmful substances and maintains the homeostasis of the internal environment. Destruction of the intestinal barrier is linked to the digestive system, cardiovascular system, endocrine system, and other systemic diseases. Mounting evidence suggests that ischemic stroke not only changes the intestinal microbes but also increases the permeability of the intestinal barrier, leading to bacterial translocation, infection, and even sepsis. The intestinal barrier, as part of the gut-brain axis, has also been proven to participate in the pathophysiological process of ischemic stroke. However, little attention has been paid to it. Since ischemic stroke is a major public health issue worldwide, there is an urgent need to know more about the disease for better prevention, treatment, and prognosis. Therefore, understanding the pathophysiological relationship between ischemic stroke and the intestinal barrier will help researchers further uncover the pathophysiological mechanisms of ischemic stroke and provide a novel therapeutic target for the treatment of ischemic stroke. Here, we review the physiology and pathology between ischemic stroke and intestinal barrier based on related articles published in the past ten years about the relationship between ischemic stroke, stroke risk factors and intestinal flora, and intestinal barrier. We further discuss the following parts: the intestinal barrier, possible mechanisms of intestinal barrier destruction in ischemic stroke, intestinal barrier destruction caused by stroke-related risk factors, intestinal barrier dysfunction in ischemic stroke, targeting the intestinal barrier for improving stroke, conclusions and perspectives.

c-JNK (c-Jun N-terminal kinase) and p38 mitogen-activated protein kinase (MAPK) family members work in a cell-specific manner to regulate neuronal signals. The abnormal activation of these cellular signals can cause glutamate excitotoxicity, disrupted protein homeostasis, defective axonal transport, and synaptic dysfunction. Various pre-clinical and clinical findings indicate that the up-regulation of c-JNK and p38MAPK signaling is associated with neurological disorders. Exceptionally, a significant amount of experimental data has recently shown that dysregulated c-JNK and p38MAPK are implicated in the damage to the central nervous system, including amyotrophic lateral sclerosis. Furthermore, currently available information has shown that c- JNK/p38MAPK signaling inhibitors may be a promising therapeutic alternative for improving histopathological, functional, and demyelination defects related to motor neuron disabilities. Understanding the abnormal activation of c-JNK/p38MAPK signaling and the prediction of motor neuron loss may help identify important therapeutic interventions that could prevent neurocomplications. Based on the involvement of c-JNK/p38MAPK signaling in the brain, we have assumed that the downregulation of the c-JNK/p38MAPK signaling pathway could trigger neuroprotection and neurotrophic effects towards clinicopathological presentations of ALS and other brain diseases. Thus, this research-based review also outlines the inhibition of c-JNK and p38MAPK signal downregulation in the pursuit of disease-modifying therapies for ALS.

Aging is an important stage of the human life cycle and the primary risk factor for Neurodegenerative Diseases (ND). The aging process contributes to modifications in cells, which may lead to a lack of nutrient signaling, disrupted cellular activity, increased oxidative pressure, cell homeostasis depletion, genomic instability, misfolded protein aggregation, impaired cellular protection, and telomere reduction. The neuropathologies found in Alzheimer's Disease (AD) and Parkinson's Disease (PD) are internally and extrinsically compound environmental stressors which may be partially alleviated by using different phytochemicals. The new therapies for ND are restricted as they are primarily targeted at final disease progression, including behavioral shifts, neurological disorders, proteinopathies and neuronal failure. This review presents the role of phytochemicals-related polyphenolic compounds as an accompanying therapy model to avoid neuropathologies linked to AD, PD and to simultaneously enhance two stochastic stressors, namely inflammation and oxidative stress, promoting their disease pathologies. Therefore, this approach represents a prophylactic way to target risk factors that rely on their action against ND that does not occur through current pharmacological agents over the life of a person.

Background: In human tauopathies, pathological aggregation of misfolded/unfolded proteins, particularly microtubule-associated protein tau (MAPT, tau) is considered to be an essential mechanism that triggers the induction of endoplasmic reticulum (ER) stress. Objective: Here, we assessed the molecular effects of natural antioxidant alpha-lipoic acid (ALA) in human tau^R406W (hTau)-induced ER unfolded protein response (ERUPR) in fruit flies. Methods: In order to reduce hTau neurotoxicity during brain development, we used a transgenic model of tauopathy where the maximum toxicity was observed in adult flies. Then, the effects of ALA (0.001, 0.005, and 0.025% w/w of diet) in htau-induced ERUPR and behavioral dysfunctions in the ages 20 and 30 days were evaluated in Drosophila melanogaster. Results: Data from expression (mRNA and protein) patterns of htau, analysis of eyes external morphology as well as larvae olfactory memory were confirmed by our tauopathy model. Moreover, the expression of ERUPR-related proteins involving Activating Transcription Factor 6 (ATF6), inositol regulating enzyme 1 (IRE1), and protein kinase RNA-like ER kinase (PERK) wase upregulated and locomotor function decreased in both ages of the model flies. Remarkably, the lower dose of ALA modified ERUPR and supported the reduction of behavioral deficits in youngest adults through the enhancement of GRP87/Bip, reduction of ATF6, downregulation of PERK-ATF4 pathway, and activation of the IRE1-XBP1 pathway. On the other hand, only a higher dose of ALA affected the ERUPR via moderation of PERK-ATF4 signaling in the oldest adults. As ALA also exerts higher protective effects on the locomotor function of younger adults when htau^R406Wis expressed in all neurons (htau-elav) and mushroom body neurons (htau-ok), we proposed that ALA has age-dependent effects in this model. Conclusion: Taken together, based on our results, we conclude that aging potentially influences the ALA effective dose and mechanism of action on tau-induced ERUPR. Further molecular studies will warrant possible therapeutic applications of ALA in age-related tauopathies.

Background: Restless leg syndrome (RLS) has been recognized as a typical additional manifestation among patients with cirrhosis of the liver. RLS prevalence in liver cirrhosis further worsens the quality of life, which has already been compromised with the disease-related complications of cirrhosis itself. Aims: The study aimed to determine the frequency and severity of Restless Leg Syndrome (RLS) among patients with cirrhosis of the liver and to correlate its severity with the severity of cirrhosis. Methods: This prospective cross-sectional study was carried out at Ruth K.M. Pfau Civil Hospital (Karachi, Pakistan) from December 2019 to February 2020. Three hundred and fifteen cirrhotic patients with any etiology were included in the study after informed written consent. Restless leg syndrome with its severity was determined in all cirrhotic patients. For continuous variables, means and medians with standard deviations were calculated, while percentages and proportions were used for discrete variables. Spearman correlation was used to find significance between RLS Severity Score (RSS) and Model of End-stage Liver Disease MELD Score. A p value of < 0.05 was considered significant for all analyses. Results: The frequency of RLS among cirrhotic patients was 38.4%. More than half (54.5%) of the patients had severe RLS. Viral related hepatitis C and hepatitis B were the most common cause of cirrhosis of the liver (57.8% and 30.8%). A significant difference was found between as patients both with or without RLS in terms of age (p=0.003), gender (p=0.005), hemoglobin (p=0.00), and serum albumin (p=0.01). No significant association was found between RLS severity score and MELD Score (p=0.693). Conclusion: Prevalence of RLS is very high among cirrhotic patients, but no correlation was found between the severity of RLS and cirrhosis. Further studies should be carried out to assess the quality of life in cirrhotic patients having RLS.

Introduction: Catatonia is a psychomotor syndrome that presents with severe symptoms which can lead to dangerous and lethal conditions if not diagnosed and treated properly. SARS-- CoV-2 is a positive-sense single-stranded RNA virus that can occur in severe cases with acute pneumonia, ARDS, sepsis and septic shock. In these cases, ICU admission is necessary. Case Summary: A 59-year-old Caucasian man with septic shock and bilateral interstitial pneumonia from SARS-CoV-2 and schizotypal personality disorder presented with catatonic behaviour manifested by soporous state, response to intense painful stimuli with the opening of the eyes, execution of simple verbal commands, maintenance of the same position, catalepsy, immobility, rigidity and mutism. At the same time, there were symptoms of septic shock and catatonic symptoms, causing greater difficulty in the correct formulation of the diagnosis. During the course of his hospitalization, he was treated with asenapine 20 mg/day. The catatonia responded rapidly and significantly to the asenapine. Discussion: To date, the pathophysiology of catatonia is unclear, and few guidelines are available for the treatment of catatonia. In the literature, studies have reported the efficacy of benzodiazepines such as lorazepam and diazepam, GABAA agonists such as zolpidem, NMDA receptor antagonists such as memantine, antidepressant SSRIs such as fluoxetine and paroxetine, and antipsychotics such as olanzapine, clozapine and aripiprazole. We demonstrate that the antipsychotic asenapine is also effective in treating catatonic symptoms in psychiatric disorders. Conclusion: Asenapine produced a rapid and significant reduction in catatonic symptoms in our patient with schizotypal personality disorder.