engleski

Non-trangenic rat model of sporadic Alzhimer's disease: Is it suitable for testing of novel drug therapies?

Introduction Pathophysiology and novel drug therapies of sporadic Alzheimer’s disease (sAD) are being widely investigated in animal models. The most popular ones are transgenic mice models which are appropriate for the familiar (gene- mutation based) but not for the sporadic type of AD. Rats treated intracerebroventricularly with streptozotocin (STZ-icv) have been recently proposed as an experimental sAD model whose validation is in a progress. Methods Adult Wistar rats received icv injections of STZ (0.3-3 mg/kg) or vehicle only (controls). Additionally, STZ-icv (3 mg/kg) treated animals were given iron-chelator and antioxidant drug M30 (2 and 10 mg/kg) orally 3x weekly starting 2 weeks after the STZ-icv treatment. All animals were sacrificed 3 months after the STZ-icv treatment. Cognitive functions were tested by Passive Avoidance Test before sacrifice. Protein expression of cholinergic muscarinic M1 and nicotinic α7 receptors was measured in the hippocampus (HPC) and parietotemporal cortex (PTC) by SDS-PAGE electrophoresis and immunoblotting. Data were analysed by Kruskal-Wallis and Mann- Whitney U test (p<0.05). Results In comparison to the controls, cognitive functions in the STZ-icv treated rats were found significantly decreased with higher (1 and 3 mg/kg) STZ doses (-46.67% and -66.79%, respectively). Expression of M1 receptors was found increased with 1 and 3 mg STZ dose in PTC (+82.89% and +67.83%) and decreased in HPC (- 18.06% and 15.01%), respectively, while α7 receptor expression was unaltered. Cognitive deficits in STZ-icv treated rats were normalised with treatment of 10 mg/kg M30 dose (+314.16%). Conclusion STZ-icv rat model demonstrates dose- dependent cognitive deficits and cholinergic transmission dysfunction similar to those found in human sAD which supports its representativeness as a non- transgenic sAD animal model suitable for testing of novel drugs, like promising multifunctional M30 substance. Acknowledgement Supported by UKF, DAAD and MZOS.

streptozotocin; cholinergic; M30

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