Central Nervous System Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Central Nervous System Agents) - Volume 20, Issue 3, 2020

The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third life-threatening disease apart from stroke and cancer for the geriatric population. Till now, only four drugs are available on the market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidence of molecular targets are the major hurdles for developing a new drug to treat AD. The rate of attrition of many advanced drugs at clinical stages makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a new drug for AD by repurposing old drugs through screening and data mining. For example, the survey in the drug pipeline for Phase III clinical trials (till February 2019) consists of 27 candidates, and around half of the number are drugs which have already been approved for other indications. Although in the past, the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In this manuscript, we have reviewed the clinical candidates for AD with emphasis on their development history, including molecular targets and the relevance of the target for AD.

Background: Citrus limon a small evergreen plant belongs to the family Rutaceae. These species are extensively cultivated throughout the world because of their multiple health benefits for humans and their applications in the pharmaceutical and food industries. Various studies were conducted using their plant parts (fruits, flowers, peels, leaves, blossoms) but the studies on peel extracts are very limited. However, the anticonvulsant activity of peels has not been studied yet. Objective: The main goal of this study is to appraise the anticonvulsant effect stimulated by the antioxidant property of hydroalcoholic extracts of Citrus limon (HAECL) peels in various animal models. Methods: The anticonvulsant and in vivo antioxidant activity of HAECL peels was observed by Maximal electric shock (MES) model, pentylenetetrazole (PTZ) induced clonic convulsion model and PTZ induced kindling test. The extract was administered to test groups at doses of 200, 400 and 600 mg/kg. orally in PTZ and MES methods. The highest dose of extract was given to the test grouped animals in case of a kindling test. After completion of the time period of kindling, the brains of all grouped animals were isolated and subjected to analyse oxidative stress parameters such as malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and glutathione (GSH) biochemically to investigate the antioxidant profile of the plant. Results: HAECL peels at doses of 400 and 600 mg/kg significantly (p<0.01) delayed the onset, decreased the duration of myoclonic spasm in PTZ induced seizure model and also significantly (p<0.01) decreased the duration of hind limb tonic extension (HLTE) as well as significantly (p<0.05) increased the postictal depression (PID) in MES model compared to control. In the PTZinduced kindling model, the malondialdehyde (MDA) level was elevated with a diminished level of SOD, CAT, GSH compared to the control group but pretreatment with HAECL at the highest dose reduced the MDA level and refined SOD, CAT and GSH status effectively. Conclusion: From the above investigation, it was concluded that HAECL could produce significant anticonvulsant activity and also attenuate oxidative stress-induced during a seizure.

Background: Putranjiva roxburghii Wall is traditionally known to cure many pathological conditions including epilepsy. Objective: The present study is aimed at determining bioactive compounds in ethanolic extract of Putranjiva roxburghii test extract (PRTE) seeds by GCMS analysis and to assess its antiepileptic potential using various experimental models of epilepsy. Methods: The ethanolic extract of seeds of Putranjiva roxburghii was subjected to GC-MS analysis to detect the bioactive phytoconstituents. Acute oral toxicity of the extract was performed using OCED guideline 420. Pentylenetetrazol (PTZ) kindling model of epilepsy and Maximal electroshock epilepsy (MES) model of epilepsy were used to determine anti-epileptic potential. Results: The GC-MS analysis of the extract revealed the presence of 20 phytoconstituents. The major phytoconstituents included n-Propyl heptyl ether (25.25%), 5-Ethyl hydantoin (8%), octadec- 9-enoic acid (16.25%) and 1, 2-Benzene dicarboxylic acid (11.86%). The PRTE (50 mg/kg and 100 mg/kg) afforded a significant and dose-dependent protection against PTZ-induced kindling epilepsy and MES induced epilepsy (p<0.001 and p<0.01). Conclusion: Based on the above findings, it is evident that Putranjiva roxburghii seeds contain biologically active compounds. It can also be concluded that the extract possesses anti-epileptic potential.

Objective: The study was designed to investigate the anti-nociceptive activity of Euphorbia hirta leaf and its possible mechanism of action. Methods: The extract of Euphorbia hirta obtained from the leaf was prepared as per standard procedures and evaluated at the three doses (300, 600, and 1200 mg/kg, i.p). The extract was screened for anti-nociceptive activity using heat-induced (tail-flick) and chemical-induced (acetic acid-induced writhing and formalin-induced paw lick) nociception models in mice. The possible mechanism of action of the extract was evaluated using antagonists of notable nociceptive pathways. Results: Intraperitoneal administration of Euphorbia hirta extract at the doses of 600 and 1200 mg/kg significantly (p<0.05) reduced the formalin-induced paw licking in both neurogenic and inflammatory phases of the test. While administration of the extract at the dose of 300 mg/kg significantly inhibited the pain due to formalin in the inflammatory phase but not in the neurogenic phase. The anti-nociceptive effect of Euphorbia hirta extract increased the reaction time to thermal stimulus, also inhibited the acetic acid-induced writhing dose-dependently. The antinociceptive effect exhibited by Euphorbia hirta extract in the formalin test was reversed by the administration of naloxone, theophylline, and atropine. Glibenclamide, nifedipine, and yohimbine, however, did not significantly block the anti-nociceptive effect of the extract. Meanwhile, methylene blue administration enhanced the anti-nociceptive effect of the extract. Conclusion: The results indicated that Euphorbia hirta extract produces a dose-related antinociceptive effect in several models of chemical and thermal pain, through mechanisms that might involve interaction with adenosine, cholinergic, and opioid receptors.

Background: Chronic stress elevates the cortisol beyond normal levels, which affects cognition including learning & memory. This injurious effect is primarily mediated via over excitation of metabotropic glucocorticoid receptors (mGR). Methods: The present study was aimed to appraise the neuroprotective effects of naturally occurring molecule β-1,3-glucan by interfering with stress-cortisol-mGR axis. Our data of virtual screening (in silico) exhibited the promising interactions of β-glucan with the mGR. Therefore, the study was extended to evaluate its efficacy (2.5, 5 and 10 mg/kg/ i.p) in an animal model of chronic unpredictable mild stress (CUMS, 28 days) induced memory impairment. Results: Results of the current study revealed the β-glucan provided dose dependent protection against deleterious effects of stress on learning and memory associated parameters observed in Morris water maze (MWM) task. At higher tested doses, it has also significantly antagonized the stress induced weight loss and corticosterone elevation.

Background: AMD is becoming one of the leading causes of blindness in older adults. The prevalence rate of the wet form of AMD has been increasing due to the lack of selective therapeutic modalities. Current therapeutic interventions such as drugs targeting VEGF, and VEGF receptors, laser coagulants delivered unsuccessful clinical outcomes in AMD patients. Hence, the cost-effective anti-oxidant therapeutic interventions like molecular hydrogen to protect retinal pigment epithelium (RPE) by mitigating oxidative stress may deliver effective clinical outcomes in AMD patients. Methods: Female patients with late-stage AMD of age above 70 years were chosen for this case report. The patients were administered QIAPI1^©, a melanin precursor via sublingual route and the photographs were obtained for left and right eye to depict the efficacy of QIAPI1^© against the wet form of AMD. Results: The administration of QIAPI1^© extensively mitigated yellow-colored drusen accumulations in the retina, retinal edema, exudates, and hemorrhages in the right eye, but the effect was minimal in the case of left eye; the overall drusen accumulation was lesser than the first consultation. Conclusion: Current case report has concluded the intrinsic effect of melanin in producing the molecular hydrogen and chemical energy across the retinal tissues by dissociating water molecules and dissipating the drusen accumulations, retinal edema, and hemorrhages in AMD patients. Our preliminary study reported the usage of QIAPI1^© as a prospective therapeutic modality to mitigate the oxidative stress-mediated pathophysiology of the wet form of AMD.