The Protective Effect And Underlying Mechanism Of Memantine Hydrochloride On The Secondary Damage In The Ipsilateral Thalamus After Middle Cerebral Artery Occlusion In Rats

Objective:To investigate whether memantine hydrochloride has a protective effect on the secondary damage in the ipsilateral thalamus after middle cerebral artery occlusion in rats, and to explore its underlying mechanism.Methods:Thirty-six male Sprague-Dawley(SD) rats were subjected to the right distal middle cerebral artery occlusion(MCAO) by electrocoagulation and then randomly divided into four groups: sham-operated, MCAO, vehicle, and memantine groups(9 rats per each group). At 24 hours after MCAO, the memantine group was administered with memantine hydrochloride(20 mg/kg/d) by intraperitoneal injection for 7 days. At the8 th day after MCAO, neurological function was evaluated by the adhesive-removal test and the string test; the relative infart volumes and the number of intact neurons in the ventroposterior thalamus nucleus(VPN) was evaluated using Nissl staining;the levels of neurons(Neu N+ cells) and astrocytes(GFAP+ cells), the total Tau protein(Tau-5), and phosphorylated Tau at threonine 231(P-tau231) were evaluated using immunostaining; the levels of Tau-5, P-tau231, Glycogen synthase kinase-3β(GSK3β) in the thalamus were detected using immunoblotting.Results:Compared with the sham-operated group, the mean time to remove the stimulus from the left forepaw increased and the score of motor function decreased significantly in MCAO, vehicle, and memantine groups; However, the mean time to remove the stimulus in the memantine group decreased significantly when compared with the vehicle group. The number of intact neurons and Neu N+ cells were decreased significantly within the ipsilateral VPN, while these cells in thememantine group were less reduction than in the vehicle group. In contrast, the levels of GFAP+ cells, P-tau231 and GSK3β were increased significantly in MCAO,vehicle, and memantine groups. Nevertheless, the levels of GFAP+ cells,P-tau231 and GSK3β were decreased within the ipsilateral VPN in the memantine group compared with the vehicle group(all P <0.05). There were no significant differences of infart volumes among MCAO, vehicle, and memantine groups(P >0.05).Conclusions:1. Memantine hydrochloride has a protective effect on the secondary damage in the ipsilateral thalamus after MCAO in rats. It not only decreases neurons loss, but also inhibits astrocytes proliferation in the ipsilateral VPN, and it also improves the sensory function after MCAO;2. P-tau231 induced by ischemia has a harmful effect on the ipsilateral thalamus after MCAO;3. The underlying mechanism of memantine’s protective effect on the ipsilateral thalamus after MCAO might be related to inhibiting the activity of GSK3β and downregulating the levels of P-tau231 protein.