Abstract: Overloading of intracellular Ca2+ in the brain might be responsible for the occurrence of some brain dysfunctions. Nimodipine, a dihydropyridine calcium channel antagonist, has a potent vasodilatory effect on expanding cerebral vessels and increasing cerebral blood flow. It is also able to block the voltage-dependent L-type channels. Its antiepileptic properties have been shown in various animal models, including Ca2+-induced seizures in adult mice and rats. As a result, there has been a great deal of interest in potential beneficial effects of nimodipine on CNS function. Several lines of investigation have shown that nimodipine administration is beneficial in brain dysfunction associated with trauma or aging. The purpose of the present study was to further investigate the synaptic mechanisms of nimodipine in ameliorating CaCI2-induced memory dysfunction in brain. Male Kun Ming mice were divided into 3 groups: control (n = 10), CaCI2 group (n = 12), and CaCI2+nimodipine group (n = 11). These groups were injected with physiological saline (intrahippocampally), CaCI2 (2.9ug per mouse, treated intrahippocampally), CaCI2 (2.9ug per mouse, treated intrahippocampally) and nimodipine (2ug per mouse, ip), respectively. Memory retention was assessed using a one-trial passive avoidance response task. After the experiment, the animals were killed and the hippocampus of each was prepared for transmission electron microscopy. The structural parameters of the Gray I synaptic interface in the hippocampal CA3 areas of mice were observed and analyzed quantitatively by a transmission electron microscope and XY-biological image analysis system. The main results were as follows:
(1) Compared to that of the control group, the STL of the CaCI2 group was greatly shortened in one trial passive avoidance response (p<0.01). The thickness of postsynaptic density (PSD) of this group was thinned significantly (p<0.001). The width of the synaptic cleft showed a robust increase (p<0.01). The number of the flat synapses was significantly increased (p<0.05), while the numbers of the negative curve synapses and perforated synapses were also reduced (p<0.05).
(2) Compared to that of the CaCI2 group, the STL of CaCI2+nimodipine group was long in one trial passive avoidance response (p<0.01), indicating that nimodipine was able to ameliorate chemical memory dysfunction. Accordingly, there were the reverse changes of the structural parameters of the Gray I synaptic interface in the CaCI2+nimodipine group compared with the above-mentioned pathological changes in the CaCI2 group. The treatment of nimodipine was able to antagonize the pathological morphology changes caused by CaCI2.
These results suggest that the reverse of the structural parameters of the Gray I synaptic interface in the hippocampal CA3 areas might be the morphological foundation of the amelioration of calcium antagonist-nomodipine on memory deficit caused by the injection of CaCI2. However, further experimental studies are needed to investigate the mechanisms of nimodipine in ameliorating CaCI2-induced memory dysfunction in the brain

Key words: nimodipine, mice, CaCI2, memory dysfunction, synapse