Chronic inhibition of central Angiotensin-converting enzyme ameliorates colchicine-induced memory impairment in mice

Abstract

Preclinical and clinical studies indicated involvement of the central renin-angiotensin system (RAS) in memory functions. However, the role of central angiotensin-converting enzyme (ACE) in memory function is still unclear. The present study investigated the involvement of central ACE in colchicine-induced memory impairment in the context of cholinergic function and oxidative stress. Memory impairment was induced by intracerebral colchicine administration in mice. The ACE inhibitor, perindopril (0.05 and 0.1 mg/kg/day), was administered orally for 14 days. Memory function was evaluated by the Morris water maze (MWM) test from the 14(th) day on after colchicine injection. Donepezil was used as a standard. Parameters of oxidative stress and cholinergic function, ACE activity in serum and the brain were estimated after the completion of behavioral studies. Colchicine caused memory impairment as revealed by no significant change in latency to reach a hidden platform in the MWM test. Furthermore, there was a significant increase in MDA, ROS, and nitrite levels with a reduction in GSH level and acetylcholinesterase (AChE) activity in the brain of colchicine-treated mice. Colchicine significantly increased brain ACE activity without affecting serum ACE. Donepezil prevented colchicine-induced memory impairment in mice. The antidementic effect of perindopril may be attributed to reduced oxidative stress and improvement in cholinergic function. Moreover, the elevated brain ACE activity was also inhibited by perindopril. The study showed that central ACE plays an important role in colchicine-induced memory deficit, corroborating a number of studies that show that treatment with ACE inhibitors could be neuroprotective.

Keywords: Acetylcholinesterase; Oxidative stress; Perindopril; Renin angiotensin system.

Fig. 1

Standardization of colchicine-induced memory impairment model in mice. Results were expressed as mean latency time (sec) ± S.E.M. ^*P < 0.05 and ^**P < 0.05 in comparison to session 1.

Fig. 2

Effect of perindopril on colchicine-induced memory impairment in mice. Results were expressed as mean latency time (sec) ± S.E.M. ^*P < 0.05 and ^**P < 0.05 in comparison to session 1.

Fig. 3

a: Effect of perindopril pretreatment on serum ACE activity in colchicine (IC) induced memory deficit mice. Serum ACE activity was expressed as mean Units/liter ± S.E.M. ^*P<0.05 in comparison to control and vehicle groups and ^#P<0.05 in comparison to colchicine group. b: Effect of perindopril pretreatment on brain ACE activity in colchicine (IC) induced memory deficit mice. Brain ACE activity was expressed as mean Units/mg protein ± S.E.M. ^#Significant increase (^#P<0.05) in comparison to control group and ^*P<0.05 in comparison to colchicine (IC) group.

Fig. 4

Effect of perindopril on MDA (nmol/mg protein) level in mice brain. Results were expressed as mean ± S.E.M. ^#Significant difference (^#P<0.01) vs control and aCSF group and ^*P < 0.01 vs colchicine group.

Fig. 5

Effect of perindopril on GSH (μg/mg protein) level in mice brain. Results were expressed as mean ± S.E.M. ^#Significant difference (^#P<0.01) vs control and aCSF group and ^*Significant difference (^*P < 0.05 and **P<0.01) vs colchicine group.

Fig. 6

Effect of perindopril on nitrite (μg/mg protein) level in mice brain. Results were expressed as mean ± S.E.M. ^#Significant difference (^#P<0.01) vs control and aCSF group and ^*P<0.01 vs colchicine group.

Fig. 7

Effect of perindopril on ROS (% of control) level in mice brain. Results were expressed as mean ± S.E.M. ^#Significant difference (^#P<0.01) vs control and aCSF group and *P<0.01 vs colchicine group.

Fig. 8

Effect of perindopril on AChE activity (μg/min/mg protein) in mice brain. Results were expressed as mean ± S.E.M. ^#Significant difference (^#P<0.01) vs control and aCSF group and *P<0.01 vs colchicine group.