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1. Prophylaxis with Bacopa monnieri Attenuates Acrylamide Induced Neurotoxicity and Oxidative Damage via Elevated Antioxidant Function

Author(s): George Kunnel Shinomol, Narayanareddy Raghunath, Muchukunte Mukunda Srinivas Bharath and Muralidhara

Affiliation: Department of Neurochemistry, National Institute of Mental Health and Neurosciences (NIMHANS), No. 2900, Hosur Road, Bangalore-560029, India.

Abstract

Acrylamide (ACR) is a water-soluble, vinyl monomer that has multiple chemical and industrial applications. Exposure to ACR causes neuropathy and associated neurological defects including gait abnormalities and skeletal muscle weakness, due to impaired neurotransmitter release and eventual neurodegeneration. Using in vivo and in vitro models, we examined whether oxidative events are involved in ACR-mediated neurotoxicity and whether these could be prevented by natural plant extracts. Administration (i.p.) of ACR in mice (40 mg/kg bw/ d for 5d) induced significant oxidative damage in the brain cortex and liver as evidenced by elevated lipid peroxidation, reactive oxygen species and protein carbonyls. This was associated with lowered antioxidant activities including antioxidant enzymes (catalase, glutathione-s-transferase) and reduced glutathione (GSH) compared to untreated controls. Similarly, exposure of N27 neuronal cells in culture to ACR (1-5 mM) caused dose-dependent neuronal death and lowered GSH. Interestingly, dietary supplementation with the leaf powder of Bacopa monnieri (BM) (which possesses neuroprotective properties and nootropic activity) in mice for 30 days offered significant protection against ACR toxicity and oxidative damage in vivo. Similarly, pretreatment with BM protected the N27 cells against ACR-induced cell death and associated oxidative damage. Co-treatment and pre-treatment of Drosophila melanogaster with BM extract protected against ACR-induced locomotor dysfunction and GSH depletion. We infer that BM displays prophylactic effects against ACR induced oxidative damage and neurotoxicity with potential therapeutic application in human pathology associated with neuropathy.

2. Effect of Withania somnifera Supplementation on Rotenone-Induced Oxidative Damage in Cerebellum and Striatum of the Male Mice Brain

Author(s): Mallaya Jayawanth Manjunath and Muralidhara

Affiliation: Department of Biochemistry and Nutrition, CSIR- Central Food Technological Research Institute (CFTRI), Mysore- 570020, India.

Abstract

Withania somnifera (WS) an ayurvedic medicinal herb is widely known for its memory enhancing ability and improvement of brain function. In the present study, we tested the hypothesis that WS prophylaxis could offset neurotoxicant-induced oxidative dysfunctions in developing brain employing a rotenone (ROT) mouse model. Initially, we assessed the potential of WS oral supplements (100-400 mg/ kg b.w/ d, 4wks) to modulate the endogenous levels of oxidative markers in cerebellum (cb) and striatum (st) of prepubertal (PP) mice. Further, we assessed the induction of oxidative stress in cb and st of mice administered with ROT (i.p. 0.5 and 1mg/ kg b.w, 7d). ROT caused significant elevation in the levels of reactive oxygen species (ROS), malondialdehyde (MDA), hydroperoxides (HP) and nitric oxide (NO) levels in both brain regions. Further ROT caused significant perturbations in the levels of reduced glutathione (GSH), activity levels of antioxidant enzymes, acetylcholinesterase and mitochondrial dysfunctions suggesting a state of oxidative stress. In a satellite study, we examined the protective effects of WS root powder (400mg/ kg b.w/ d, 4wks) in PP mice challenged with ROT (0.5 mg/ kg b.w/ d, 7 d). WS prophylaxis significantly offset ROT-induced oxidative damage in st and cb as evident by the normalized levels of oxidative markers (MDA, ROS levels and HP) and restoration of depleted GSH levels. Further, WS effectively normalized the NO levels in both brain regions suggesting its antiinflammatory action. Furthermore, WS prophylaxis restored the activity levels of cytosolic antioxidant enzymes, neurotransmitter function and dopamine levels in st. Taken together, these findings suggest that WS prophylaxis has the propensity to modulate neurotoxicant-mediated oxidative impairments and mitochondrial dysfunctions in specific brain regions of mice. While the exact mechanism/s underlying the neuroprotective effects of WS merit further investigation, based on our findings, we hypothesize that it may be wholly or in part due to its ability to enhance GSH, thiols and antioxidant defences in the brain of mice.

3. Acetylcholinesterase Inhibitors from QSAR Point of View: How Close are We?

Author(s): Anuradha Sharma and Poonam Piplani

Affiliation: Rayat-Bahra Institute of Pharmacy, Hoshiarpur, India.

Abstract

In view of the large libraries of acetylcholinesterase inhibitors (AChEIs) that are now being handled in organic synthesis, the identification of drug biological activity is advisable prior to synthesis and this can be achieved by employing predictive biological property methods. In this sense, Quantitative Structure–Activity Relationships (QSAR) or docking approaches have emerged as promising tools. The intention of this review is to summarize the present knowledge concerning computational predictions of AChEIs and AChE.

4. Semicarbazone Analogs as Anticonvulsant Agents: A Review

Author(s): Mohamed Jawed Ahsan

Affiliation: Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Jaipur, Rajasthan 302 023, India.

Abstract

Semicarbazones are synthesized by the condensation of semicarbazide and aldehyde/ketone. The literature survey revealed that semicarbazones had been emerged as compounds with diverse biological activities including anticonvulsant, antitubercular, anticancer, and antimicrobial activities. The anticonvulsant activity of semicarbazones is mainly attributed due to the presence of an aryl binding site with aryl/alkyl hydrophobic group, a hydrogen bonding domain and an electron donor group and they are suggested to act by inhibiting sodium ion (Na+) channel. Dimmock et al., reported an extensive series of semicarbazones and reported 4-(4-fluorophenoxy) benzaldehyde semicarbazone (C0102862, V102862) as lead molecule. In MES (oral) screening C0102862 showed protective index (PI > 315) more than carbamazepine (PI 101), phenytoin (PI > 21.6) and valproate (PI > 2.17). This review briefly describes the information available about semicarbazone analogs and their anticonvulsant activity.

5. In Silico Validation and Structure Activity Relationship Study of a Series of Pyridine-3-carbohydrazide Derivatives as Potential Anticonvulsants in Generalized and Partial Seizures

Author(s): Reema Sinha, Udai Vir Singh Sara, Ratan Lal Khosa, James Stables and Jainendra Jain

Affiliation: Department of Pharmacy, RamEesh Institute of Vocational and Technical Education, 3, Knowledge Park I, Greater Noida, Gautam Budh Nagar, Uttar Pradesh, India-201310.

Abstract

A series of twelve compounds (Compounds RNH1–RNH12) of acid hydrazones of pyridine-3-carbohydrazide or nicotinic acid hydrazide was synthesized and evaluated for anticonvulsant activity by MES, scPTZ, minimal clonic seizure and corneal kindling seizure test. Neurotoxicity was also determined for these compounds by rotarod test. Results showed that halogen substitution at meta and para position of phenyl ring exhibited better protection than ortho substitution. Compounds RNH4 and RNH12, were found to be the active analogs displaying 6Hz ED50 of 75.4 and 14.77 mg/kg while the corresponding MES ED50 values were 113.4 and 29.3 mg/kg respectively. In addition, compound RNH12 also showed scPTZ ED50 of 54.2 mg/kg. In the series, compound RNH12with trifluoromethoxy substituted phenyl ring was the most potent analog exhibiting protection in all four animal models of epilepsy. Molecular docking study has also shown significant binding interactions of these two compounds with 1OHV, 2A1H and 1PBQ receptors. Thus, N-[(meta or para halogen substituted) benzylidene] pyridine-3-carbohydrazides could be used as lead compounds in anticonvulsant drug design and discovery.

6. Psychomotor Seizure Test, Neurotoxicity and in vitro Neuroprotection Assay of some Semicarbazone Analogues

Author(s): Mohamed Jawed Ahsan and James P. Stables

Affiliation: Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Jaipur, Rajasthan 302 023, India.

Abstract

In continuance of our search for anticonvulsant agents, we reported herein the synthesis, characterization and anticonvulsant evaluation of some newer semicarbazone analogues. A few compounds were also screened for neuroprotection assay. Some of the compounds showed significant anticonvulsant activity. Compound 4a showed 25% (1/4, 0.25 h), 75% (3/4, 0.5 & 2.0 h) and 100% (4/4, 1.0 h) protection against 6 Hz psychomotor seizure test at 100 mg/kg devoid of any neurotoxicity. Compound 4d showed neuroprotection activity with 26.3 ± 2.3 percent of total propidium iodide uptake at 100 μ M and IC50 of the compound was calculated using dose response curve by probit analysis and was found to be 149 ± 1.22 μ M.

For details on the journal, please visit: Central Nervous System Agents in Medicinal Chemistry