Neuroprotective effects of growth hormone against methylmalonic acid-mediated hippocampal damage in methylmalonic aciduria: implication of NRF2/HO-1 pathway.
Lu Xiangpeng, Wang Yanfei, Sun Jianhua, Bai Huanghuang, Zhang Qiuwen, Wang Jili, Wang Zheng, Zheng Hong
Abstract
Methylmalonic aciduria is an inherited metabolic disease accompanied by hippocampal damage and neurological impairment. Growth hormone (GH) has been reported to play important roles in the nervous system, but its role and underlying mechanism in methylmalonic aciduria remains poorly understood. Here, a rat model of methylmalonic aciduria was established via subcutaneous injection of methylmalonic acid (MMA). GH treatment improved cognitive function and spatial memory and alleviated hippocampal neuronal damage in MMA rats. GH also reduced oxidative stress and mitochondrial dysfunction in the hippocampal tissues, as evidenced by decreased levels of ROS and MDA, attenuated loss of mitochondrial membrane potential (ΔΨm), and increased SOD, CAT, GSH and ATP. In addition, MMA-induced apoptosis, oxidative stress and mitochondrial dysfunction were prevented by GH treatment in PC12 cells. Notably, GH upregulated the expression of NRF2 and HO-1 in both MMA rats and MMA-treated PC12 cells. Rescue experiments further indicated that the protective effects of GH in PC12 cells might be mediated via the NRF2 pathway. In summary, our findings demonstrated that GH attenuates MMA-induced oxidative stress and mitochondrial dysfunction through the NRF2/HO-1 pathway. This study highlights the potential mechanisms underlying the beneficial effects of GH in methylmalonic aciduria.
Key Findings
- Growth hormone (GH) treatment improved cognitive function and spatial memory in a rat model of methylmalonic aciduria.
- GH alleviated hippocampal neuronal damage by reducing oxidative stress and mitochondrial dysfunction, evidenced by decreased ROS and MDA levels and increased antioxidant enzymes (SOD, CAT, GSH) and ATP.
- GH upregulated NRF2 and HO-1 expression, and the protective effects against apoptosis and oxidative stress in PC12 cells were mediated via the NRF2 pathway.
Clinical Significance
The study suggests that growth hormone may offer a therapeutic strategy to mitigate oxidative stress and mitochondrial dysfunction in methylmalonic aciduria through activation of the NRF2/HO-1 pathway, potentially improving neurological outcomes.
Citation
Lu Xiangpeng, Wang Yanfei, Sun Jianhuaet al.. Neuroprotective effects of growth hormone against methylmalonic acid-mediated hippocampal damage in methylmalonic aciduria: implication of NRF2/HO-1 pathway. Neurotoxicology. 2026-Nov-01.