PPAR-γ/SGK1/GSK3β/Nrf2 signaling pathway contributes to the neuroprotective effects of lycopene in depressed mice.

INTRODUCTION Major depressive disorder (MDD) is a neuropsychiatric disorder associated with abnormal neuronal activity in specific brain regions. Recent evidence suggests that oxidative stress- and neuroinflammation-driven impairments in synaptic structure and neuronal function may contribute to depression, yet the precise mechanisms remain unclear. Lycopene (LYC) is a lipophilic dietary carotenoid that exhibits strong neuroprotective and antioxidant properties.

Objectives

Here, we report that LYC alleviates chronic stress-induced neuroinflammation, oxidative stress, and impaired synaptic transmission by activating the PPAR-γ/SGK1/p-GSK3β/Nrf2/HO-1 signaling pathway.

Methods

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Results

Integrated transcriptomic and network pharmacology analyses prioritized PPAR-γ as a potential target of LYC. Moreover, pharmacological activation of PPAR-γ induced LYC-like effects by alleviating chronic stress-induced behavioral deficiency, oxidative stress and neuroinflammation, whereas CA1-local inhibition of PPAR-γ weakened LYC-mediated neuroprotection effects. Electrophysiological data further suggest that chronic stress weakened synaptic transmission and excitability in CA1 pyramidal neurons, while LYC improved the neuronal dysfunction through a PPAR-γ/SGK1/p-GSK3β/Nrf2/HO-1 signaling.

Conclusions

These findings demonstrate that LYC activates the PPAR-γ/SGK1/p-GSK3β/Nrf2/HO-1 signaling pathway to alleviate chronic stress-induced oxidative stress and neuroinflammation, thereby improving neuroplasticity and protecting against stress-related depression.