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Rapamycin Effectively Impedes Melamine-Induced Impairments of Cognition and Synaptic Plasticity in Wistar Rats
Jingxuan Fu1, Hui Wang1, Jing Gao2
1College of Life Sciences and Key Laboratory of Bioactive Materials Ministry of Education, Nankai University, 300071, Tianjin, People's Republic of China.
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.
Insights
Rapamycin, an autophagy activator, protects neurons from melamine toxicity by improving cognitive function and synaptic plasticity in rats. This study highlights autophagy regulation as a potential therapy for melamine-induced neurotoxicity.
Area of Science:
- Neuroscience
- Toxicology
- Cell Biology
Background:
- Melamine exposure induces neurotoxicity, causing cell death and cognitive impairment.
- Autophagy plays a protective role against melamine-induced cell death by inhibiting reactive oxygen species (ROS).
Purpose of the Study:
- To investigate the neuroprotective effects of rapamycin, an autophagy activator, against melamine-induced cognitive and synaptic impairments in rats.
- To explore the underlying mechanisms, including oxidative stress and apoptosis.
Main Methods:
- Wistar rats were administered melamine (300 mg/kg/day for 4 weeks) with or without rapamycin (1 mg/kg/day for 28 days).
- Cognitive function was assessed using the Morris water maze test.
- Hippocampal synaptic plasticity (LTP and depotentiation), autophagy markers, oxidative stress markers (ROS, superoxide dismutase, malondialdehyde), and caspase-3 activity were evaluated.
Main Results:
- Melamine impaired spatial learning, reversal learning, and hippocampal synaptic plasticity.
- Rapamycin treatment significantly improved cognitive function and alleviated synaptic plasticity impairments.
- Rapamycin increased autophagy markers, decreased ROS and malondialdehyde levels, increased superoxide dismutase activity, and reduced caspase-3 activity.
Conclusions:
- Rapamycin exerts neuroprotective effects against melamine toxicity by enhancing autophagy, reducing oxidative stress, and inhibiting apoptosis.
- Autophagy regulation represents a promising therapeutic strategy for mitigating melamine-induced neurotoxicity and cognitive deficits.
