Norepinephrine modulates the microglial response and protects against MPTP-induced Parkinson's disease pathology through regulation of the PI3K/AKT/mTOR pathway.
Norepinephrine modulates the microglial response and protects against MPTP-induced Parkinson's disease pathology through regulation of the PI3K/AKT/mTOR pathway.
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Dongfeng, CN · Author affiliation
Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan 442008, Hubei, PR China; Institute of Neuroscience, Hubei University of Medicine, Shiyan, Hubei Province, China.Location evidence
CN · Author affiliation · country only
Institute of Neuroscience, Hubei University of Medicine, Shiyan, Hubei Province, China. Electronic address: Yunfu_wang2025@163.com.Location evidence
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Original abstract
AIMS: Norepinephrine (NE) deficiency is an early and prominent feature of Parkinson's disease (PD), but its specific contributions to pathogenesis have not been fully elucidated. This study aims to determine whether NE exerts neuroprotective effects in PD models through the modulation of autophagy and microglial activation mediated by the PI3K/Akt/mTOR pathway. METHODS: C57BL/6 mice were randomly assigned to four experimental groups: control group, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD model group, MPTP + DOPS (droxidopa) treatment group, and MPTP + DOPS +3-MA (3-methyladenine) treatment group. A comparative analysis was conducted across the four groups to evaluate clinical symptoms, concentration of NE, α-synuclein (α-syn) aggregation levels, the number of dopaminergic neurons in the substantia nigra (SN), autophagy activity, microglial activation states, and the expression of key components of the PI3K/Akt/mTOR signaling pathway. For the in vitroexperiments, BV2 microglial cells were assigned to four groups: control, LPS-treated, LPS + NE -treated, and LPS + NE + 3-MA-treated, the activation state of BV2 cells, intracellular reactive oxygen species (ROS) levels, and the expression of autophagy-related markers were assessed. Finally, the protein expression levels of key components within the PI3K/Akt/mTOR pathway were analyzed in BV2 microglial cells across the following groups: control, LPS-treated, LPS + NE-treated, and LPS + NE + PI3K activator-treated. RESULTS: Compared with the MPTP-induced model group, the MPTP+DOPS treatment group exhibited significant neuroprotective effects, as evidenced by ameliorated behavioral deficits, restored NE levels, reduced α-syn aggregation, increased survival of dopaminergic neurons, enhanced autophagic activity, and a shift in microglia toward an anti-inflammatory phenotype (p < 0.05). Conversely, autophagy inhibitor with 3-MA abolished the protective effects of DOPS, leading to exacerbated behavioral impairment, reduced NE levels, promoted α-syn accumulation, aggravated loss of dopaminergic neurons, and a shift in microglial polarization toward a pro-inflammatory state compared to the MPTP+DOPS group (p < 0.05). These in vivo findings were consistently recapitulated in vitro experiments. Meanwhile, DOPS treatment significantly reduced the p-mTOR in vivo (p < 0.05), and this suppression was abolished by 3-MA co-treatment (p < 0.05). This mechanistic link was further supported in vitro, where application of a PI3K activator led to increased p-mTOR expression (p < 0.05). CONCLUSION: Our findings demonstrate that NE confers protection against PD-related pathologies by promoting autophagy via inhibition of the PI3K/Akt/mTOR pathway. This intervention simultaneously induces a microglial phenotype switch from pro-inflammatory to anti-inflammatory, thereby suppressing neuroinflammation, α-syn deposition, and the loss of dopaminergic neurons.