Effect Of Calpain Inhibitor MDL28170 On Learning And Memory Ability And The Beta-amyloid Peptide Deposition In Hippocampal Region Of Rats

The most common neurodegenerative disease worldwide is Alzheimer's disease(AD),which is characterized by loss of hippocampal neurons and synapses resulting in progressive cognitive impairment,loss of memory,lack of language skills,and reduced reasoning leading to dementia and finally death.AD is characterized by two pathological hallmarks consisting of extracellular plaques of amyloid-βpeptide(Aβ) aggregates and intracellular neurofibrillary tangles(NFTs)composed of hyperphosphorylated microtubular protein tau.Calpain is a calcium(Ca²⁺)-dependent cysteine protease.Various studies show how calpains,acting directly or indirectly through other proteolytic pathways and cellular signaling cascades,may promoteβ-amyloidogenesis,neurofibrillary pathology and mediate neurodegeneration in AD.Calpains appear to play an important role in apoptosis in many cases and lead to neurodegenerative pathologies such as AD.Current understanding of the molecular mechanisms in AD strongly suggests calpain activation in neurodegeneration and calpain inhibition as a possible approach for the treatment of AD.ObjectivesTo establish experimental animal model in accord with the praxiological and pathological characteristics of AD;To investigate the effect of calpain inhibitor MDL28170 on the deposition of Aβand apoptotic neuronal cell death.MethodsSeventeen male Sprague-Dawley rats were randomly assigned to three experimental groups:control group(NS),Aβinfusion group(AB) Aβcoinfusion with calpain inhibitor group(CI).Animals from AB,CI and NS group were infused with Aβ,MDL28170 together with Aβand normal saline respectively into the right hippocampus of each rat.Water maze test were employed to investigate ability of learning and memory in rats,image pattern analysis quantitative method were used to detect the number of apoptosis neuron in hippocampus(TUNEL).The sections of the brain were examined with methyl-alcohol-Congo staining to observe the aggradation of Aβ.Results1.Morris water maze test Learning scores:After 6 days training,the escape latency in AB rats was significantly longer compared with that in NS and CI rats(p＜0.05);2.Morris water maze test memory scores:The number of times of crossing the platform in AB group(1.38±0.92)was significantly reduced compared with that in NS group[(9.00±2.65),p＜0.05]and CI group[(8.67±2.73),p＜0.05];The percentage of time spent on crossing the target quadrant to the total swimming time in AB group (21.13±3.53)was also significantly decreased compared with that in NS [(38.00±7.04),P＜0.01]group and CI group[(43.33±12.03),P＜0.01].2.Morphology change(1).Aβdeposition,neurons death and glial reaction in CI group were significantly decreased compared with that in AB group;(2).The number of infiltrated glial cells around the Aβaggradation site in the AB group were significantly increased than that of the CI group[(276.37±36.33)vs(187.93±21.81)cells/field,P＜0.01].3.The number of TUNEL positive neuron in hippocampus of AB group(38.92±8.81)is obviously higher than CI(20.63±5.28)group,the difference between the two groups is statistically significant(P＜0.01).Conclusions1.The infused Aβin the hippocampus is related to the impairment of learning and memory and the neuronal degeneration in the rats which showed similar behavior and pathological characterizations of AD.This Aβinfused rats could be used as an animal model for AD to Probe the neurotoxic mechanisms of AD and its treatments.2.Calpain inhibitor MDL28170 can reduce the deposition of Aβin the hippocampus and significantly improve the ability of learning and memory of Aβrats.3.Calpain inhibitor MDL28170 appears to play an important role in apoptosis and is a neuron protection factor for AD.