CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 20, Issue 10, 2021

Cobb Syndrome (Spinal Arteriovenous Metameric Syndrome 1-31 (SAMS 1-31)) is a rare, non-hereditary disorder. Approximately 100 cases of CS have been described to date. The actual incidence may be much higher since only symptomatic patients were documented. In particular, post mortem studies suggest a possibly higher incidence of this syndrome. The main clinical manifestations of this syndrome include skin stains of vascular nature on the torso, in combination with spinal vascular malformations localized in one and the same metameric or spinal segment. A rare diagnosis of this syndrome in patients over 18 is probably related to the fact that the disease may be asymptomatic throughout a long period of time, while patients may tend to disregard the skin lesions. As a result, most publications on this pathology are based on separate case reports. Significant variability of clinical manifestations as well as prolonged progress of the disease often cause errors in diagnosis. What follows is a case report of a young patient with Cobb Syndrome, who was admitted to a regional vascular centre with a misdiagnosis of stroke. 20 patients of young age (from 20 to 35 years old), with a diagnosis of stroke, who were admitted to a University Clinic (of the Russian National Research Medical University Named After Pirogov N.I., Moscow). Among this group of patients, a patient with Cobb syndrome was identified. Patient P., of 22 years, presented with acute, intensive cervical spinal pain, predominantly on the right, numbness and weakness in the arms and legs. About 3 weeks before admission to the hospital, the patient had ARVI with a fever of up to 37.5°C: two weeks before the onset of symptoms, he had undergone extirpation of 2 teeth, for which reason he spent over 2 hours in a forced position with his head thrown back (prolonged overextension in the cervical spine). Multiple skin angiomas on the chest spreading to the shoulder and scapula region. Tetraparesis up to 4 points: tetraparesis in hands with low muscle tone, low reflexes, tetraparesis in legs with high muscle tone, high reflexes, foot clonus when causing Achilles reflexes, tremor in the extremities and no plantar reflex pathology were detected, sensitivity disorders in the hands “the high gloves” and no pelvic disorders were detected. Given the presence and exacerbation of neurological symptoms and cutaneous angiomas, MRI with a contrast agent of the cervical spine was recommended. MR-image of an advanced arteriovenous malformation (AVM) of the cervical spinal cord with signs of gliosis and spinal cord oedema at the C2-C7 level. Endovascular embolization of the AVM in the cervical spinal cord was performed. The treatment led to the complete reversal of neurological symptoms. In the presence of skin lesions, the diagnosis of CS does not present particular difficulties, so in children and young patients with skin angiomatosis, it is advisable to conduct a comprehensive examination using selective spinal angiography or MR angiography to exclude arteriovenous malformations in the spinal cord.

Huntington’s disease (HD) is a progressive neurodegenerative disorder which deteriorates the physical and mental abilities of the patients. It is an autosomal dominant disorder and is mainly caused by the expansion of a repeating CAG triplet. A number of animal models ranging from worms, fruit flies, mice and rat, pig, sheep and monkeys are available, which have been helpful in understanding various pathways involved during the progression of the disease. Drosophila is one of the most commonly used model organisms for biomedical science, due to low cost maintenance, short life span and easy implications of genetic tools. The present review provides a brief description of HD and the studies carried out for HD to date, taking Drosophila as a model.

Alzheimer’s Disease (AD) is one of the major neurodegenerative disorders. Deposition of amyloid fibrils and tau protein is associated with various pathological symptoms. Currently, limited medication is available for AD treatment. Most of the drugs are basically cholinesterase inhibitors and associated with various side effects. Natural plant products have shown potential as a therapeutic agent for the treatment of AD symptoms. A variety of secondary metabolites such as flavonoids, tannins, terpenoids, alkaloids, and phenols are used to reduce the progression of the disease. Plant products have fewer or no side effects and are easily available. The present review gives a detailed account of the potential of natural plant products against AD symptoms.

Background and Objective: Neurological diseases are becoming a significant problem worldwide, with the elderly at a higher risk of being affected. Several researchers have investigated the neuroprotective effects of Carvacrol (CAR) (5-isopropyl-2-methyl phenol). This review systematically surveys the existing literature on the impact of CAR when used as a neuroprotective agent in neurological diseases. Methods: The systematic review involved English articles published in the last ten years obtained from PubMed, Google Scholar, and Scopus databases. The following descriptors were used to search the literature: “Carvacrol” [Title] AND “neuroprotective (neuroprotection)” [Title] OR “stroke, traumatic brain injury, Alzheimer's disease, Parkinson's disease, seizure, epilepsy [Title]. Results: A total of 208 articles were retrieved during the search process, but only 20 studies met the eligibility criteria and were included for review. A total of 20 articles were identified, in which the efficacy of CAR was described in experimental models of stroke, traumatic brain injury, Parkinson’s disease, Alzheimer’s disease, epilepsy, and seizure, through motor deficits improvements in neurochemical activity, especially antioxidant systems, reducing inflammation, oxidative stress and apoptosis as well as inhibition of TRPC1 and TRPM7. Conclusion: The data presented in this study support the beneficial impact of CAR on behavioural and neurochemical deficits. CAR benefits accrue because of its anti-apoptotic, antioxidant, and anti- inflammatory properties. Therefore, CAR has emerged as an alternative treatment for neurological disorders based on its properties.

Background: A dimeric dipeptide mimetic of the BDNF loop 4, bis(N-monosuccinyl- L-seryl-L-lysine) hexamethylenediamide (GSB-106) activates TrkB, PI3K/AKT, MAPK/ ERK, and PLC-γ1, and was created at the V.V. Zakusov Research Institute of Pharmacology. GSB-106 showed neuroprotective activity in vitro and in vivo at systemic administration. Objective: In this work, we studied the GSB-106 effect on the cerebral infarct volume, as well as on neurogenesis and synaptogenesis under the experimental ischemic stroke induced by intravascular occlusion of the middle cerebral artery in rats. Methods: GSB-106 was administered i.p. in a dose of 0.1 mg/kg, 24 h after the surgery and then once a day, with the end of administration on day 6 after surgery. On day 7, brain samples were collected for morphometric and biochemical (Western-blot) analysis. Results: It was established that GSB-106 reduced the brain damage volume by 24%, restored impaired neurogenesis and/or gliogenesis (by Ki-67) in the hippocampus and the striatum, and completely restored the reduced immunoreactivity to synaptic markers synaptophysin and PSD-95 in the striatum. Conclusion: Thus, the dimer dipeptide BDNF mimetic GSB-106 exhibits neuroregenerative properties at a clinically relevant time window (24 h) in a model of ischemic stroke presumably due to the stimulation of neurogenesis (and/or gliogenesis) and synaptogenesis.

Background: Dementia is a neurodegenerative disorder majorly evidenced by cognitive impairment. Although there are many types of dementia, the common underlying etiological factors in all the types are neuro-inflammation or aging induced apoptosis. β-caryophyllene, a cannabinoid type-2 receptor agonist, has been reported to have promising neuroprotective effects in cerebral ischemia and neuro-inflammation. Objective: In the present study, we evaluated the effects of β-caryophyllene against animal models of dementia whose etiology mimicked neuro-inflammation and aging. Methods: Two doses (50 and 100 mg/kg of body weight) of β-caryophyllene given orally were tested against AlCl3-induced dementia in male Sprague Dawley (SD) rats using the Morris water maze test. Subsequently, the effect of the drug was assessed for episodic memory in female SD rats using novel object recognition task in doxorubicin-induced neuro-inflammation and chemobrain model. Moreover, its effects were evaluated in D-galactose-induced mitochondrial dysfunction leading to dementia. Results: β-caryophyllene, at both doses, showed significant improvement in memory when assessed using parameters like target quadrant entries, escape latency and path efficiency in the Morris water maze test for spatial memory. In the doxorubicin-induced chemobrain model, β-caryophyllene at 100 mg/kg significantly elevated acetylcholinesterase and catalase levels and lowered lipid peroxidation compared to the disease control. In the novel object recognition task, β-caryophyllene at 100 mg/kg significantly improved recognition index and discrimination index in the treated animals compared to the disease control, with a significant increase in catalase and a decrease in lipid peroxidation in both hippocampus and frontal cortex. However, in the D-galactose-induced mitochondrial dysfunction model, β-caryophyllene failed to show positive effects when spatial memory was assessed. It also failed to improve D-galactose-induced diminished mitochondrial complex I and II activities. Conclusion: Hence, we conclude that β-caryophyllene at 100 mg/kg protects against dementia induced by neuro-inflammation with no effect on neuronal aging induced by mitochondrial dysfunction.

Background: Obsessive-Compulsive Disorder (OCD) is an intricate, debilitating neuropsychiatric disorder. Exclusively, Selective Serotonin Reuptake Inhibitors (SSRIs) are effective agents used for the treatment of OCD. However, SSRIs are not a magic pill-they do not respond adequately to everybody. In this consideration, a single drug target (magic bullet) is only a slightly superior option for all patients with a lot of pathognomonic signs. Objective: The principal aim of the current study was to check the potential contribution of repurposing of magic shotgun nature of curcumin (rhizomes of Curcuma longa) with scattergun approach- proceeding a pioneer ‘fine-tune’ for obsessive-compulsive disorder. Method: Swiss albino mice (male 20 to 25 gram) were grouped into different groups (n = 6) used for the MBB (marble-burying behaviour) and MA (motor activity) test as a model for evaluation of anti-compulsive activity (Anti-OCD). Ethanolic extract of Curcuma longa (EECL-10, 15, 25, 40 mg/kg), or SSRI (fluoxetine 5, 10, 15 mg/kg) followed by pre-treated with either sub effective dose of fluoxetine attenuated MBB without effected the MA, or neurotoxin p-chlorophenyl alanine induced compulsive behavior and specific 5-HT receptors agonists/ antagonist, intraperitoneally revealed neuromodulation. Results: EECL (40 mg/kg) significantly attenuated the MBB. Although, during treatments, none of the above had any critical impact on MA. p < 0.05 was considered significant in every case. Conclusion: Multiple drug-target interactions with multifarious biogenic receptors, supervene unexpected side effects followed by the repurposing of wanted effects (scattergun effect) were evoked by curcumin treatment. Finally, the study shows that EECL (curcumin) has anti-compulsive activity, which is mediated by neuromodulation with 5-HT receptors.

Background: Psychosocial stress-induced depressive behavior is linked to the etiology of several neurological diseases viz., PTSD, and neurodegenerative disease like Alzheimer's Disease (AD). The repeated bouts of social stress defeat can be induced using Resident-Intruder- Paradigm (RIP) and Chronic Mild Social Stress (CMSS) animal models to assess the stress-induced depressive behavioral patterns. Objectives: The aim of this study to examine the anti-depressive efficacy of 3-methoxythietane- 1,1-dioxide (N-14) in RIP models of behavioral alterations. Methods: In this study, we have used Sprague-Dawley rats in Resident-Intruder-Paradigm (RIP), where intruders interacted with residents Day 0 to Day +5 for 10 minutes to invoke CMSS in intruders and became defeated/submissive rats due to the depressive-like behavioral alterations in social activity, explorations, grooming, defense, aggressive behavior, social interaction, freeze, rearing etc., with residents. Control intact animals are included in group I, group II received N-14 alone; group III received CMSS, and group IV received cotreatment of N14 with CMSS. N-14 (2 mg/kg) was administered intraperitoneally from Day 0 to Day +5 to intact animals and intruder animals under conditions of CMSS. Results: Several behavioral tests viz., forced swim test, open field test, and elevated-plus maze test were used to examine the above behavioral dynamic parameters. The dynamic interaction between Residents and Intruders during the study showed substantial alterations in exploratory activity, aggressiveness, defensive behavior, body weight, and thymus mass in stressed animals. N-14 cotreatment has mitigated sociability, exploratory activity, aggressiveness increased social adaptability and defensive behavior. An extensive rise in active forms of defense and submission latency indicates that N-14 has induced antidepressant activity with a psycho-sedative component of action. Conclusion: Serendipitously, we observed the ameliorative capability of N-14 cotreatment to mitigate depressive-behavioral symptoms in intruders.