montelukast and Cognition-Disorders

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.

Topics: Acetates; Animals; Carotid Artery Diseases; Cerebral Cortex; Cholinergic Agents; Cognition Disorders; Cyclopropanes; Disease Models, Animal; Glutathione; Leukotriene Antagonists; Lipid Peroxidation; Male; Mice; Oxidative Stress; Oxidoreductases; Quinolines; Receptors, Leukotriene; Ruthenium Red; Ryanodine Receptor Calcium Release Channel; Sulfides; Time Factors

Topics: Acetates; Aging; Alzheimer Disease; Animals; Anti-Asthmatic Agents; Cognition Disorders; Cyclopropanes; Estrogens; Female; Hippocampus; Humans; Inflammation Mediators; Leukotrienes; Macaca mulatta; Male; Mice; Neuronal Plasticity; Parkinson Disease; Plasma; Prefrontal Cortex; Quinolines; Rats; Rejuvenation; Sulfides; Synapses

There is an evolving consensus that mild cognitive impairment (MCI) serves as a prodrome to Alzheimer's disease. Antioxidants and COX-2 (cyclo-oxygenase-2) inhibitors have also been reported to have beneficial effects against conditions of memory impairment. Newer drugs like cysteinyl leukotriene inhibitors have shown neuroprotective effect in animal models of ischemia. Thus, the present study purports to explore the potential role of montelukast (a cysteinyl leukotriene inhibitor) in concert with rofecoxib (COX-2 inhibitor) and caffeic acid (a 5-LOX inhibitor and potent antioxidant) against kainic acid induced cognitive dysfunction in rats. In the experimental protocol, kainic acid (0.4 μg/2 μl) in artificial cerebrospinal fluid (ACSF) was given intrahippocampally (CA3 region) to induce a condition similar to MCI. Memory performance was measured on days 10-14 and the locomotor activity was measured on days 1, 7 and 14. For estimation of biochemical, mitochondrial and histopathological parameters, animals were sacrificed on day 14, stored at -80 °C and the estimation was done on the 15th day. The treatment groups consisting of montelukast (0.5 and 1 mg/kg), rofecoxib (5 and 10 mg/kg) and caffeic acid (5 and 10 mg/kg) showed significant improvement in memory performance, oxidative stress parameters and mitochondrial function as compared to that of control (kainic acid treated), however, combination of montelukast with rofecoxib showed significant improvement in their protective effect. Thus the present study emphasizes the positive modulation of cysteinyl leukotriene receptor inhibition on COX (cyclooxygenase) and LOX (lipoxygenase) pathways in the control of the neuroinflammation in kainic acid induced cognitive dysfunction in rats.

Topics: Acetates; Acetylcholinesterase; Animals; Antioxidants; Caffeic Acids; Cognition Disorders; Cyclooxygenase 2 Inhibitors; Cyclopropanes; Drug Synergism; Glutathione; Hippocampus; Kainic Acid; Lactones; Leukotriene Antagonists; Lipoxygenase Inhibitors; Maze Learning; Memory; Motor Activity; Neuroprotective Agents; Neurotoxins; Oxidation-Reduction; Oxidative Stress; Quinolines; Rats; Rats, Wistar; Sulfides; Sulfones; Tumor Necrosis Factor-alpha