capsazepine and Brain-Ischemia

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel with high Ca(2+) permeability, which functions as a polymodal nociceptor activated by heat, protons and several vanilloids, including capsaicin and anandamide. Although TRPV1 channels are widely distributed in the mammalian brain, their pathophysiological roles in the brain remain to be elucidated. In this study, we investigated whether TRPV1 is involved in cerebral ischemic injury using a middle cerebral artery (MCA) occlusion model in wild-type (WT) and TRPV1-knockout (KO) mice. For transient ischemia, the left MCA of C57BL/6 mice was occluded for 60 min and reperfused at 1 and 2 days after ischemia. We found that neurological and motor deficits, and infarct volumes in TRPV1-KO mice were lower than those of WT mice. Consistent with these results, intracerebroventricular injection of a TRPV1 antagonist, capsazepine (20 nmol), 30 min before the onset of ischemia attenuated neurological and motor deficits and improved infarct size without influencing cerebral blood flow in the occluded MCA territory. The protective effect of capsazepine on ischemic brain damage was not observed in TRPV1-KO mice. WT and TRPV1-KO mice did not show any differences with respect to the increased number of Iba1-positive microglia/macrophages, GFAP-positive astrocytes, and Gr1-positive neutrophils at 1 and 2 days after cerebral ischemia. Taken together, we conclude that brain TRPV1 channels are activated by ischemic stroke and cause neurological and motor deficits and infarction after brain ischemia.

Topics: Animals; Brain Ischemia; Capsaicin; Mice; Mice, Inbred C57BL; Mice, Knockout; TRPV Cation Channels

Recently, a potential neuroprotective effect of rimonabant, independent of the CB1 receptor interaction, has been proposed. In the present study, the role of transient receptor potential channel vanilloid subfamily member 1, named VR1, on neuroprotective effect of rimonabant, on global cerebral ischemia in gerbils, was investigated. Rimonabant (0.05-3 mg kg-1), given i.p. 5 min after recirculation, dose dependently antagonized the ischemia-induced decrease in electroencephalographic (EEG) total spectral power and restored relative frequency band distribution 7 days after ischemia. Rimonabant (0.125-0.5 mg kg-1) fully prevented ischemia-induced hyperlocomotion 1 day after ischemia and memory impairment evaluated in a passive avoidance task, 3 days after ischemia. At 7 days after ischemia, the survival of pyramidal cells, in the CA1 subfield, was respectively 91 and 96%, in the animals given rimonabant 0.25 and 0.5 mg kg-1, compared to the vehicle group. Higher doses were not protective. The protection induced by rimonabant followed a bell-shaped curve, the maximal active doses being 0.25 and 0.5 mg kg-1. Capsazepine (0.01 mg kg-1), a selective VR1 vanilloid receptor antagonist, completely reversed rimonabant-induced neuroprotective effects against EEG flattening, memory impairment and CA1 hippocampal neuronal loss. These findings suggest that VR1 vanilloid receptors are involved in rimonabant's neuroprotection even if other mechanisms can contribute to this effect.

Topics: Animals; Avoidance Learning; Brain Ischemia; Cannabinoid Receptor Antagonists; Capsaicin; Electroencephalography; Gerbillinae; Male; Motor Activity; Neuroprotective Agents; Piperidines; Pyrazoles; Rimonabant; TRPV Cation Channels

We have examined the role of TRPV1 activation in disrupting the blood-brain barrier by measuring the permeability of single pial venular capillaries in anaesthetized rats. Capsaicin application to the brain surface resulted in increased permeability, maximal 2.1+/-0.12 x 10(-6) cm s(-1) (mean+/-s.e.m.) with log EC50 -4.5+/-0.10. Substance P methyl ester gave a similar response (maximal 2.0+/-0.07, n = 6, log EC50 -4.8+/-0.07), but the selective NK2 agonist, beta-Ala8-NKA(4-10) peptide, had no effect. Although CGRP decreased the permeability of venules (log EC50 10.3+/-0.11), its receptor antagonist CGRP(8-37) had no effect on the response to capsaicin. The TRPV1 antagonist capsazepine (1 mM) reduced the response to capsaicin (100 microM), from 1.78+/-0.15 to 0.63+/-0.10 (n = 4). The NK1 receptor antagonists GR205171 (100 microM) and SDZ NKT 376 (1 mM) also reduced the response to capsaicin (from 1.75+/-0.14 to 0.46+/-0.08; n = 6, and from 1.85+/-0.13 to 0.48+/-0.05; n = 5, respectively), indicating that capsaicin acts via TRPV1 in series with NK(1). Starch microspheres were used to produce transient focal ischaemia. Permeability was increased on reperfusion to a greater extent and more rapidly in vessels with diameter greater than 40 microm than those less than 15 microm. Capsazepine given intraperitoneally during ischaemia reduced the permeability increase in small venules from 5.9+/-0.3 to 2.4+/-0.1, and from 11.4+/-0.8 to 5.1+/-0.9 in large venules. In conclusion, the TRPV1 receptor is active in the brain microvasculature and has its permeability-increasing effect via substance P. It also plays a role in the immediate blood-brain barrier disruption following ischaemia-reperfusion.

Topics: Animals; Blood-Brain Barrier; Brain Ischemia; Capillaries; Capillary Permeability; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Male; Microspheres; Piperidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Starch; Substance P; Tetrazoles; Time Factors; TRPV Cation Channels