title: Melatonin receptor and KATP channel modulation in experimental vascular dementia.
abstract: Cerebrovascular and cardiovascular diseases are stated as important risk factors of vascular dementia (VaD) and other cognitive disorders. In the central nervous system, melatonin (MT1/MT2) as well as serotonin subtype 2C (5-HT2C) receptors is pharmacologically associated with various neurological disorders. Brain mitochondrial potassium channels have been reported for their role in neuroprotection. This study has been structured to investigate the role of agomelatine, a melatonergic MT1/MT2 agonist and nicorandil, a selective ATP sensitive potassium (KATP) channel opener in renal artery ligation (two-kidney-one-clip: 2K1C) hypertension induced endothelial dysfunction, brain damage and VaD. 2K1C-renovascular hypertension has increased mean arterial blood pressure (MABP), impaired memory (elevated plus maze and Morris water maze), endothelial function, reduced serum nitrite/nitrate and increased brain damage (TTC staining of brain sections). Furthermore, 2K1C animals have shown high levels of oxidative stress in serum (increased thiobarbituric acid reactive species-TBARS with decreased levels of glutathione-GSH, superoxide dismutase-SOD and catalase-CAT), in the aorta (increased aortic superoxide anion) and in the brain (increased TBARS with decreased GSH, SOD and CAT). 2K1C has also induced a significant increase in brain inflammation (myeloperoxidase-MPO levels), acetylcholinesterase activity (AChE) and calcium levels. Impairment in mitochondrial complexes like NADH dehydrogenase (complex-I), succinate dehydrogenase (complex-II) and cytochrome oxidase (complex-IV) was also noted in 2K1C animals. Administration of agomelatine, nicorandil and donepezil significantly attenuated 2K1C-hypertension induced impairments in memory, endothelial function, nitrosative stress, mitochondrial dysfunction, inflammation and brain damage. Therefore, modulators of MT1/MT2 receptors and KATP channels may be considered as potential agents for the management of renovascular hypertension induced VaD.
authors: CNS and CVS Pharmacology Lab., Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology, Partapur Bypass, Meerut, 250103 Uttar Pradesh, India. Electronic address: sharmaslab2@gmail.com.
authors: Prabhat
authors: P
authors: Singh
authors: CNS and CVS Pharmacology Lab., Department of Pharmacology, School of Pharmacy, Bharat Institute of Technology, Partapur Bypass, Meerut, 250103 Uttar Pradesh, India. Electronic address: sharmaslab3@gmail.com.
authors: Surbhi
authors: S
authors: Gupta
authors: School of Pharmacy, Bharat Institute of Technology, Partapur Bypass, Meerut, 250103 Uttar Pradesh, India; CNS Pharmacology, Conscience Research, Pocket F-233, B, Dilshad Garden, Delhi 110095, India. Electronic address: drbhupeshresearch@gmail.com.
authors: Bhupesh
authors: B
authors: Sharma
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D062186:Arterial Pressure / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015140:Dementia, Vascular / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006978:Hypertension, Renovascular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D054086:KATP Channels / Q000819:agonists* / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D020108:Nicorandil / Q000494:pharmacology; D018697:Nootropic Agents / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D017208:Rats, Wistar; D044094:Receptors, Melatonin / Q000819:agonists* / Q000378:metabolism*; D065852:Spatial Memory / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D054086:KATP Channels; D018696:Neuroprotective Agents; D020108:Nicorandil; D018697:Nootropic Agents; D044094:Receptors, Melatonin; C084711:agomelatine; D009281:Naphthalenes
keywords: Acetylcholinesterase; Agomelatine; Donepezil; Mitochondrial enzyme complex; Myeloperoxidase; Nicorandil