Capsaicin exhibits neuroprotective effects in a model of transient global cerebral ischemia in Mongolian gerbils

Abstract

1. Capsaicin, the irritant principle of hot peppers, is a vanilloid agonist known to activate the transient receptor potential channel vanilloid subfamily member 1 (VR1), recently reported to be involved in neurodegeneration. The present study investigated the role of VR1 in a model of global cerebral ischemia in gerbils. 2. Over the dose range tested, capsaicin (0.01, 0.025, 0.05, 0.2 and 0.6 mg kg(-1)), given 5 min after recirculation, dose-dependently antagonized the ischemia-induced electroencephalographic total spectral power decrease and restored relative frequency band distribution evaluated 7 days after ischemia. 3. Capsaicin, at all tested doses, fully prevented ischemia-induced hyperlocomotion evaluated 1 day after ischemia. 4. Capsaicin dose-dependently antagonized ischemia-induced memory impairment evaluated in a passive avoidance task, 3 days after ischemia. 5. Capsaicin showed a dose-dependent hypothermic effect evaluated for 2 h after recirculation. 6. At 7 days after ischemia, a progressive survival of pyramidal cells in the CA1 subfield in capsaicin-treated gerbils, with a maximum of 80%, at a dose of 0.2 mg kg(-1), was obtained. 7. The selective VR1 antagonist, capsazepine (0.01 mg kg(-1)), reversed capsaicin-induced protective effects, in a competitive manner. 8. These results suggest that the neuroprotective effect of capsaicin may be attributable, at least in part, to VR1 desensitization and provide a valuable target for development of interventional pharmacological strategies.

Figure 1

Cortically derived EEG total spectral power evaluated as the difference (Δ%) from the preischemic value in freely moving awake gerbils given increasing doses (mg kg⁻¹) of capsaicin 5 min after recirculation either singly or in combination with CPZ at a dose of 0.01 mg kg⁻¹ administered s.c. 15 min before bilateral carotid occlusion. Veh=vehicle. Each column represents the mean (±s.e.m.) of five animals. ^aP<0.001 compared with sham;^bP<0.001 compared with capsaicin 0.2 and 0.6; ^cP<0.001 compared with vehicle; ^dP<0.05, ^eP<0.001 in comparison with CPZ+capsaicin (one-way ANOVA followed by Tukey's test).

Figure 2

Effect of increasing doses (mg kg⁻¹) of capsaicin given s.c. 5 min after recirculation either singly or in combination with CPZ at a dose of 0.01 mg kg⁻¹ administered s.c. 15 min before bilateral carotid occlusion on spontaneous motor activity evaluated for 30 min, 1 day after ischemia in gerbils. Veh=vehicle. Each column represents the total number of horizontal counts (mean±s.e.m.) of five animals. ^aP<0.001 compared with sham; ^bP<0.001 compared with corresponding capsaicin alone; ^cP<0.01, ^dP<0.001 compared with vehicle (one-way ANOVA followed by Tukey's test).

Figure 3

Escape latency evaluated in the passive avoidance task 3 days after ischemia. Increasing doses (mg kg⁻¹) of capsaicin were given s.c. 5 min after recirculation either singly or in combination with CPZ at a dose of 0.01 mg kg⁻¹ administered s.c. 15 min before bilateral carotid occlusion. Veh=vehicle. Each column represents the mean (±s.e.m.) of five animals. ^aP<0.01, ^bP<0.001 compared with sham; ^cP<0.001 compared with corresponding capsaicin alone; ^dP<0.001 compared with vehicle (one-way ANOVA followed by Tukey's test).

Figure 4

Effect of increasing doses (mg kg⁻¹) of capsaicin given s.c. 5 min after recirculation either singly or in combination with CPZ at a dose of 0.01 mg kg⁻¹ administered s.c. 15 min before bilateral carotid occlusion on changes from baseline in rectal temperature. Veh=vehicle. Rectal temperatures were measured starting from 5 min after recirculation. Each column represents the mean (±s.e.m.) of five gerbils. ^aP<0.05, ^bP<0.01, ^cP<0.001 compared with sham; ^dP<0.001 compared with corresponding capsaicin alone (two-way ANOVA followed by Bonferroni's test).

Figure 5

Photomicrographs of the hippocampal CA1 region of gerbils with or without 10-min ischemia, evaluated 7 days after ischemia. (a) Sham-operated animal. (b) Ischemic animal treated with vehicle 5 min after recirculation. (c) Ischemic animal treated with capsaicin (0.2 mg kg⁻¹) 5 min after recirculation. (d) Ischemic animal treated with CPZ (0.01 mg kg⁻¹) and capsaicin. Bar=50 μm.

Figure 6

Effect of increasing doses of capsaicin (mg kg⁻¹) on neuronal count evaluated 7 days after recirculation in the CA1 region of the hippocampus of sham-operated or ischemic gerbils. Capsaicin was given s.c. 5 min after recirculation. For the antagonism, capsaicin (0.2 mg kg⁻¹) was given in combination with CPZ at a dose of 0.01 mg kg⁻¹ given s.c. 15 min before bilateral carotid occlusion. Each column represents the mean (±s.e.m.) of five hippocampal sections from the same coronal plane for each animal. n=5 for each group. ^aP<0.05, ^bP<0.001 compared with sham; ^cP<0.05, ^dP<0.01, ^eP<0.001 compared with vehicle; ^fP<0.001 compared with capsaicin alone (one-way ANOVA followed by Tukey's test).