engleski

Alteration of memory functions and cholinergic transmission in the brain of the streptozotocin-induced rat model of sporadic Alzheimer’s disease

INTRODUCTION: The ethiopathogenesis of sporadic Alzheimer’s disease (sAD) is unknown and the onset and development of its pathophysiological hallmarks are difficult for tracking in humans. There is a need for the representative animal sAD model which should be well characterized and validated as a model suitable for novel drug testing. Rats treated intracerebroventricularly with streptozotocin (STZ-icv) have been recently proposed as a non-transgenic sAD model which demonstrates AD-like pathology. We aimed to characterize the STZ-icv dose- and post-treatment time-dependency of cognitive impairment and cholinergic deficit in the brain of the STZ-icv rat model. MATERIALS AND METHODS: Adult Male Wistar rats were injected bilaterally icv with STZ (0.3, 1 and 3 mg/kg) or vehicle (controls) and sacrificed one week, and one, three, six and nine months after the treatment. Cognitive deficits were measured by Passive Avoidance Test (PA). Acetylcholinesterase (AChE) activity was measured in hippocampus (HPC) and cortex (CTX) by Ellman’s method. Protein expression of muscarinic cholinergic receptor M1 in the HPC and CTX was measured by SDS-PAGE electrophoresis, followed by Western blot analysis. Data were analysed by Kruskal-Wallis and Mann-Whitney U test (p<0.05). RESULTS: STZ-icv rats exhibit significant dose- and time-dependent cognitive deficits in PA test (40-90%). AChE activity in the STZ-icv treated rats was significantly elevated in HPC after one week (22%), one (20%) and nine (32%) months (3 mg/kg) and in PTC after six months (10% /0, 3 mg/kg ; 28% /1 mg/kg). One and 3 mg STZ dose significantly altered the expression of muscarinic M1 receptors three months after the injection, manifested as increment in CTX (+82, 89% and +67, 83%) and decrement in HPC (-18, 06% and 15, 01%), while after 9 months, the expression of M1 receptor in CTX was decreased with all three STZ doses (-22, 5%/0.3 mg/kg, -20, 39%/1 mg/kg and -18, 34%/3 mg/kg). DISCUSSION: STZ-icv rat model demonstrates long-term cognitive and hippocampal cholinergic deficits which tend to correlate mutually at the highest STZ dose regimen, varying from the acute response followed by normalization and finally progressive decompensation effects. Acknowledgements: Supported by UKF and MZOS (108-1080003-0020).

sporadic Alzheimer’s disease; intracerebroventricular streptozotocin; memory; cholinergic transmission

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