Rapamycin Effectively Impedes Melamine-Induced Impairments of Cognition and Synaptic Plasticity in Wistar Rats

Abstract

Our previous investigation demonstrated that autophagy significantly reduced melamine-induced cell death in PC12 cells via inhibiting the excessive generation of ROS. In the present study, we further examine if rapamycin, used as an autophagy activator, can play a significant role in protecting neurons and alleviating the impairment of spatial cognition and hippocampal synaptic plasticity in melamine-treated rats. Male Wistar rats were divided into three groups: control, melamine-treated, and melamine-treated + rapamycin. The animal model was established by administering melamine at a dose of 300 mg/kg/day for 4 weeks. Rapamycin was intraperitoneally given at a dose of 1 mg/kg/day for 28 consecutive days. The Morris water maze test showed that spatial learning and reversal learning in melamine-treated rats were considerably damaged, whereas rapamycin significantly impeded the cognitive function impairment. Rapamycin efficiently alleviated the melamine-induced impairments of both long-term potentiation (LTP) and depotentiation, which were damaged in melamine rats. Rapamycin further increased the expression level of autophagy markers, which were significantly enhanced in melamine rats. Moreover, rapamycin noticeably decreased the reactive oxygen species level, while the superoxide dismutase activity was remarkably increased by rapamycin in melamine rats. Malondialdehyde assay exhibited that rapamycin prominently reduced the malondialdehyde (MDA) level of hippocampal neurons in melamine-treated rats. In addition, rapamycin significantly decreased the caspase-3 activity, which was elevated by melamine. Consequently, our results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by melamine.

Autophagy attenuates postoperative cognitive dysfunction by up-regulating cystatin C in aged rats undergoing splenectomy

“…Exposing aged rats to propofol inhibits autophagy and significantly impairs cognitive performance, which is substantially improved by pretreating animals with the autophagy activator diaminodiphenyl sulfone [11]. Similarly, we found that giving rats rapamycin enhanced autophagy and ameliorated spatial learning and memory after splenectomy, consistent with studies in aged rats given rapamycin and 3-MA and subjected to exploratory laparotomy under anesthesia with 3% sevoflurane 30 min late, and melamine-treated rats given rapamycin to attenuate impairment of spatial cognition and hippocampal synaptic plasticity [22,23].…”

The Role of Cathepsins in Memory Functions and the Pathophysiology of Psychiatric Disorders

“…synaptic vesicles) ( 23 ). Congruently, pharmacological upregulation of autophagy by rapamycin alleviated deficits in synaptic plasticity and improved cognitive impairments in male rats ( 24 ). The etiology and pathophysiology of psychiatric disorders is still very limited, but it was shown that impaired autophagy might contribute to the pathophysiology of psychiatric disorders, including schizophrenia ( 25 ), major depressive disorder ( 26 ), and bipolar disorder ( 27 ).…”

Enriched environment and social isolation affect cognition ability via altering excitatory and inhibitory synaptic density in mice hippocampus

“…After 3 months of treatment, the hippocampus of mouse was separated and stored at -80 °C for the preparation of tissue lysates (n=3). The method of protein extraction was described in our previous studies [30,31]. Each hippocampus was mashed with a grinder and 200 μl lysis buffer (Beyotime Biotechnology, Haimen, China) containing 1% Phenyl methane sulfonyl fluoride (PMSF).…”