Reversal in Cognition Impairments, Cholinergic Dysfunction, and Cerebral Oxidative Stress Through the Modulation of Ryanodine Receptors (RyRs) and Cysteinyl Leukotriene-1 (CysLT1) Receptors.
Chronic cerebral hypoperfusion (CCH) is a general pathophysiological condition occurring in vascular dementia (VaD) associated with negative impact on cognitive functions. Ryanodine as well as cysteinyl leukotriene-1 receptors (RyRs and CysLT1Rs) are extensively present in the central nervous system, where they participate in regulation of cognition, motivation, inflammation and neurodegeneration. The purpose of this study is to examine the role of ruthenium red; a selective RyR blocker as well as montelukast; a specific CysLT1 antagonist in CCH induced VaD in mice. Two vessel occlusion (2VO) or permanent ligation of bilateral common carotid arteries technique was used to induce CCH in mice. Animals with bilateral carotid arteries occlusion have revealed impaired learning and memory (Morris water maze), cholinergic dysfunction (increased acetylcholinesterase activity) as well as increased brain oxidative stress (reduction in brain superoxide dismutase, glutathione and catalase with an increase in thiobarbituric acid reactive substance level), with increased brain infarct size (2,3,5-triphenylterazolium chloride staining). While, administration of ruthenium red and montelukast considerably attenuated CCH induced cognitive impairments, cholinergic dysfunction, brain oxidative stress as well as brain damage. The results suggest that bilateral carotid arteries occlusion induced CCH has brought out VaD, which was attenuated by treatment with ruthenium red and montelukast. Therefore, modulation of RyRs as well as CysLT1 receptors may provide help in conditions involving CCH such as cognitive impairment and VaD.
Prabhat
P
Singh
Department of Pharmacology, Amity Institute of Pharmacy, Amity University Uttar Pradesh, A-Block, Ground Floor, Sector-125, Noida - 201303, Uttar Pradesh, India. drbhupeshresearch@gmail.com.
Bhupesh
B
Sharma
D000085:Acetates / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002340:Carotid Artery Diseases / Q000150:complications / Q000378:metabolism / Q000473:pathology; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D018678:Cholinergic Agents / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology*; D003521:Cyclopropanes; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D020024:Leukotriene Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D010088:Oxidoreductases / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D018077:Receptors, Leukotriene / Q000378:metabolism*; D012430:Ruthenium Red / Q000494:pharmacology / Q000627:therapeutic use; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D013440:Sulfides; D013997:Time Factors
D000085:Acetates; D018678:Cholinergic Agents; D003521:Cyclopropanes; D020024:Leukotriene Antagonists; D011804:Quinolines; D018077:Receptors, Leukotriene; D019837:Ryanodine Receptor Calcium Release Channel; D013440:Sulfides; D012430:Ruthenium Red; D010088:Oxidoreductases; D005978:Glutathione; C083169:leukotriene D4 receptor; C093875:montelukast