TARGETING ALPHA-SYNUCLEIN AND NEUROINFLAMMATION: THE ROLE OF CURCUMA LONGA IN PARKINSON’S DISEASE

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which there is a loss of dopaminergic neurons in the SNpc along with intraneuronal aggregation of α-synuclein, chronic microglial-mediated neuroinflammation, and severe mitochondrial oxidative stress. Available pharmacotherapies, mostly levodopa and dopamine agonists, only provide symptomatic benefit and do not slow or stop the progression of neurodegeneration, and they also have motor complications and non-motor symptom progression. This review critically analyzes the neuroprotective potential of Curcuma longa (turmeric) and its major bioactive curcuminoids namely curcumin, demethoxycurcumin and bisdemethoxycurcumin in preclinical and clinical models of PD. The analysis is based on in vitro, in vivo and human studies published between 2010 and 2025 that have shown curcumin has multi-targeted neuroprotective properties with several well-defined molecular mechanisms. In particular, curcumin has been shown to directly inhibit α-synuclein fibrillisation and induce disaggregation of preformed fibrils, to suppress microglial activation by down-regulating NF-κB, to activate the Nrf2/antioxidant response element (ARE) pathway leading to up-regulation of phase II detoxifying enzymes and to restore mitochondrial complex I activity and to contribute to reduced reactive oxygen species generation. Although these are promising preclinical studies, the poor oral bioavailability of curcumin due to its low aqueous solubility, rapid glucuronidation by the liver and rapid efflux from the intestine by p-glycoprotein (Pgp), have made the translation to clinical practice for PD difficult. As a result, clinical trials in humans have shown conflicting findings with small improvements in Unified Parkinson's Disease Rating Scale (UPDRS) scores. However, recent evidence of brain penetration of nanocurcumin, especially in the context of intranasally delivered formulations such as nanoparticles and liposomes, has yielded much greater brain penetration, and even the first positive phase 2 clinical results. Turmeric derivatives are thus still promising as adjunctive drugs, and continued developments of bioengineered drug nanocarriers are gradually overcoming the bioavailability challenges to allow for effective clinical translations