Pharmacol Rep. 2025 Nov 7. doi: 10.1007/s43440-025-00799-2. Online ahead of print.

ABSTRACT

Parkinson’s disease (PD) is the second most common neurodegenerative disorder worldwide, characterized by debilitating motor and non-motor symptoms. Its complex pathogenesis involves dopaminergic neuron degeneration, α-synuclein aggregation, neuroinflammation, oxidative stress, and mitochondrial dysfunction. Current symptomatic treatments offer limited symptom improvement, highlighting the urgent need for new strategies, including lifestyle modifications. The ketogenic diet (KD), a dietary approach that shifts the body’s primary energy source from glucose to ketone bodies (KBs) like β-hydroxybutyrate (β-HB), has demonstrated significant therapeutic potential. This review explores KD as a promising, multifaceted intervention for PD. The potential beneficial impact of KD on PD stems from several key mechanisms. β-HB exhibits potent anti-inflammatory properties, reducing pro-inflammatory cytokines and microglial activation by inhibiting pathways such as NF-κB and NLRP3 inflammasome. The diet also improves mitochondrial function by enhancing electron transport chain activity and increasing ATP synthesis, which is crucial given the mitochondrial deficits observed in PD. Furthermore, KBs directly alleviate oxidative stress through enhanced antioxidant defenses. KD offers neuroprotection for dopaminergic neurons, provides an alternative fuel source to the brain, and optimizes cerebral glucose metabolism. It also boosts levels of essential neurotrophic factors, including brain-derived neurotrophic factor (BDNF). Beyond direct neurological effects, KD may enhance levodopa efficacy by improving its bioavailability and appears to play a crucial role in modulating gut microbiota dysbiosis, a frequently observed and potentially contributing factor in PD. While further research is essential, the comprehensive effects of KD on PD-related pathophysiology position it as a promising non-pharmacological strategy.

PMID:41201763 | DOI:10.1007/s43440-025-00799-2

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