CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 20, Issue 2, 2021

COVID-19 is one of the most disastrous respiratory diseases (after the 1918 influenza outbreak) spreading in the community. So far, it has killed 7,37,417 individuals. High variability in the viral genome and its greater ability to spread in the human community are badly affecting the comorbid individuals. Although infected individuals mainly possess respiratory issues, neurological manifestations in these individuals cannot be overlooked. The literature search is based on the recent development in the concerned field. We searched databases like PubMed, Google Scholar, and ScienceDirect using the keywords “COVID-19”, “neurological manifestations”, “CNS”, and “PNS”. The major neurological complications observed in these patients are encephalitis, necrotising haemorrhagic encephalopathy, Guillain-Barré Syndrome, smell/taste impairment, epileptic seizures, and abnormal states of consciousness. COVID-19 infection is just more than a cough, fever, and respiratory illness; it can cause indirect neurological complications in infected patients. It is therefore advised to treat and have a careful observation of the COVID-19 patients for neurological manifestations.

There are different case definitions of premenstrual syndrome, one proposed by the American College of Obstetricians and Gynecologists (ACOG) and another based on the Daily Record of Severity of Problems (DRSP) scores. Here we review our recent findings indicating that the gold-standard methods to assess PMS, including ACOG, provide a high degree of false-negative findings. We propose a new case definition of the Menstrual Cycle-Associated Syndrome (MCAS), which is characterized by increased DRSP scores during the menstrual cycle and symptom that increases the week prior to the menses. The MCAS case definition was externally validated by diverse biomarkers including plasma levels of progesterone and estradiol, chemokines (e.g. CCL2, CCL5 and CCL11), epidermal growth factor, hydroperoxides, paraoxonase 1 activity and complement C4. These biomarkers as well as IgA responses to Gram-negative bacteria are significantly associated with the DRSP and its subdomains including depression, anxiety, and physiosomatic symptoms(fatigue, pain). In conclusion, we propose, a) to use the MCAS diagnosis as an indicant of menstrual cycle-related symptoms; and b) to examine the associations of the time series in the DRSP and its subdomains and those in biomarkers including distributed lag models. Aberrations in the uterine-chemokine-brain-axis underpin the pathophysiology of MCAS whereby suboptimal pre-ovulatory follicular development coupled with a relative corpus luteum insufficiency may drive increased chemokine production, lowered antioxidant defenses, neuro-oxidative stress pathways, and increased bacterial translocation. As such, we have delineated new drug targets for the treatment of MCAS. This opinion paper reviews new possible treatments that should be trialed in MCAS.

Sepsis-associated encephalopathy causes long-term health problems in patients with sepsis. This review explores the pathogenesis of sepsis-associated encephalopathy, including its effects on the blood-brain barrier, microglia activation, mitochondrial dysfunction, the inflammatory medium and neurotransmitters and its roles in amino acid balance disorders, hyperammonemia, and intestinal flora imbalance. Understanding the etiology of sepsis-associated encephalopathy may allow the development of adjunctive therapies targeting its underlying mechanism and help develop preventative strategies.

Amongst the various diseases on a global scale, the second leading cause of mortality and morbidity is ischemic stroke due to the unavailability of an effective therapy. With the growing occurrence and its related health risks along with the absence of effective therapeutics, ischemic stroke demands the continued and intensive research to explore effective and safe therapeutics. These therapies may positively affect the numerous pathways associated with neuroprotection, thus, extending the advantages to a larger population of stroke patients. Several preclinical studies employing neuroprotectants have shown promising outcomes, but failed in clinical trials either because of the lack of safety or efficacy. The Blood-Brain Barrier (BBB) restricts the delivery of various potent neuroprotectants to the specific areas of the brain. The application of nanovehicles for the delivery of drugs in the brain, however, could revolutionize the treatment of ischemic stroke. These nanovehicles loaded with the drug could readily traverse the BBB via carrier, receptor and adsorptive-mediated endocytosis into the brain without compromising the integrity of the BBB. Recent advances in neuronanotherapeutics have resulted in improved neuronal regeneration and recovery after ischemic stroke. In this review, we have attempted to discuss unexploited neuronanotherapeutics potentials to treat and manage ischemic stroke.

Over the previous years, the use of an animal model has become very common for the screening of novel drugs. Animal model represents the complex problems of humans into the simplest forms, so these can be extended further to be included in the experimental procedure. The most successful models in neuroscience, rats and mice, are undoubtedly considered as one of the best models to understand the psychology of the mammalian brain and its associated functions involved in behavioral repertoire. Moreover, recently researchers in behavioral neuroscience are focusing more on the use of aquatic animals, especially fish, as model species due to their simplicity and cost-effectiveness. Zebrafish (Danio rerio) is a tropical fish from the minnow family, a genetic structure surprisingly 84% similar to humans. It is gaining popularity as a model to study the mechanism in behavioral neuropharmacology. Moreover, zebrafish has numerous advantages over other rodent models like the ease in maintenance due to their small size, more breeding power, transparency of embryos, overall reduced cost of experimentation, and many more. Nowadays, it is considered an ideal model to study the neurobehavioral aspects with relevance to humans. It is also used in a variety of scientific studies like genetics, neuroscience, pharmacology, and toxicology. In this manuscript, we have described the feasibility and importance of zebrafish as a model for the screening of novel drugs for different neurological disorders.

Alcohol Withdrawal Syndrome (AWS) is characterized as the termination of chronic and sustained alcohol use that leads to severe symptoms of distress or loss of daily functions when less or no alcohol is consumed. It is a debilitating manifestation of alcohol dependence and responds poorly to the available clinical therapies. Alcohol drinking is continuously increasing all over the world. It causes 3.3 million deaths every year (5.9% of all deaths) and 5.1% of the global burden of disease. Alcohol Withdrawal syndrome leads to various changes in the brain's neurotransmitters system, such as GABA, glutamate, non-epinephrine, serotonin. These symptoms arose from the imbalance in brain receptors between gamma-aminobutyric acid (GABA) and N methyl aspartate (NMDA) that develop on the discontinuation of alcohol. Studies from various in vivo and in vitro animal models of alcohol withdrawal explored new targets for the treatment of alcohol withdrawal syndrome. Advancements in the elucidation of the AWS mechanism have revealed a number of key targets that hypothesize to modulate clinical status. The present review discusses the pathophysiology, neurobiology, and treatment of alcohol withdrawal syndrome and its novel targets like corticotrophin-releasing factor, sigma, melanocortin-4 receptors, opioid, potassium channels, ghrelin, and endocannabinoid receptors, and gut microbiota. This review discusses the various clinical and pre-clinical aspects related to alcohol dependence. The exploration of novel pharmacological targets may provide effective therapeutic interventions for the management of alcohol withdrawal syndrome.

Objectives: While phenobarbital (PB) is commonly used for the management of seizures in newborns and pediatrics, its administration may accompany acute poisoning. We aimed to review the literature to find out the frequency of PB poisonings in newborns and children with seizures. Method: A literature search was performed by two independent reviewers to find relevant articles about PB toxicity in neonates and pediatrics that were treated for the seizure. Results: 18 articles met the inclusion criteria and were included in this systematic review. The main reasons for PB poisoning in studied patients were therapeutic intoxication. Reported signs of PB poisoning were lethargy, sedation, lack of sucking, fever, skin rash, hepatic inflammation and alopecia. Moreover, respiratory depression, encephalopathy, myocardial failure, syndrome of inappropriate antidiuretic hormone, and coma were among the complications of acute PB toxicity in children and infants. Conclusion: PB therapy for the management of seizures in newborns and children might be associated with poisoning. Although supportive and symptomatic treatments are available for PB overdose, it should be administered with caution, using drug monitoring to avoid toxicity.

Background: Neuropathic pain is one of the contributors to the global burdens of illness. At present many patients do not achieve satisfactory pain relief even with synthetic painkillers. Taking this into consideration, it is necessary to search for natural product-derived alternative treatment with confirmed safety and efficacy. Ageratum conyzoides L is a plant often used as an analgesic in Indonesia, however, anti-neuropathic pain activity of this plant is still unknown. Objective: To determine the anti-neuropathic pain activity of the essential oil and non-essential oil component (distillation residue) of A. conyzoides L. Methods: We conducted the separation of the essential oil component from other secondary metabolites through steam distillation. Both components were tested for anti-neuropathic pain activity using chronic constriction injury animal models with thermal hyperalgesia and allodynia tests. The animals were divided into 7 test groups, namely normal, sham, negative, positive (pregabalin at 0.195 mg/20 g BW of mice), essential oil component (100 mg/kg BW), and non-essential oil component (100 mg/kg BW). Naloxone was tested against the most potent anti-neuropathic pain component (essential oil or non-essential oil) to investigate the involvement of opioid receptors. Results: The GC-MS of the essential oil component indicated the presence of 60 compounds. Meanwhile, non-essential oil components include alkaloid, flavonoid, polyphenol, quinone, steroid, and triterpenoid. This non-essential oil component contained a total flavonoid equivalent to 248.89 ppm quercetin. The anti-neuropathic pain activity test showed significantly higher activity of the essential oil component compared to the non-essential oil component and negative groups (p<0.05). Furthermore, the essential oil component showed equal activity to pregabalin (p>0.05). However, this activity was abolished by naloxone, indicating the involvement of the opioid receptor in the action of the essential oil component. Conclusion: The essential oil component of A. conyzoides L is a potential novel substance for use as anti-neuropathic pain.

Background: Morphine tolerance on long-term usage leads to chronic pain conditions. Preclinical studies demonstrated that the upregulation of HDACs is associated with a decrease in the sensitivity of μ-opioid receptors, which results in morphine tolerance. Objective: The present study was designed to assess the influence of the selected known HDAC inhibitors (NMJ2 and NMJ3) on the pain tolerance induced by chronic administration of morphine in Balb/c mice. Methods: In the present study, morphine was administered in incremental doses 1, 2, 3.6, 6.5, 11.2, 21, and 21 mg/kg daily for seven days to develop morphine tolerance. The nociceptive thresholds, analgesia, and tolerance were assessed 30 min after morphine administration alternatively from 1st day to 7th day using the hot plate and mechanical allodynia methods. Results: The morphine control group showed a reduction in the Paw Withdrawal Threshold (PWT) and the percentage Maximum Possible Effects (MPEs). In contrast, the combination of SAHA and test drugs with morphine increased the PWT and MPEs as compared to the morphine alone group. Administration of morphine alone also showed an increase in the production of the pro-inflammatory mediator, IL-6, and down-regulation of the μ-opioid receptor in the brain tissues. Treatment with HDAC inhibitors, SAHA, and test drugs showed a reversal in these changes. Conclusion: Results indicated that HDAC inhibitors were involved in the prevention of morphine tolerance in normal mice by inhibiting pro-inflammatory marker production and by increasing the sensitivity of neurons towards morphine in producing an analgesic effect in morphine tolerated mice.