Betulinic acid protects against lipopolysaccharide and ferrous sulfate-induced oxidative stress, ferroptosis, apoptosis, and neuroinflammation signaling relevant to Parkinson's Disease

Abstract

Background

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of dopaminergic neurons in the substantia nigra, leading to profound motor dysfunction and non-motor symptoms.

Objectives

Despite significant advancements in understanding PD pathophysiology, effective disease-modifying therapies remain elusive. Current research efforts are increasingly focused on developing and refining advanced in-vivo models to unravel PD mechanisms and explore novel therapeutic interventions. In this study, we investigated the neuroprotective potential of Betulinic acid (BA), a natural triterpenoid, in an experimental model of PD.

Material and methods

We evaluated the amelioration of motor impairments and associated pathological alterations in Wistar rats. The experimental model involved the administration of lipopolysaccharide (LPS) and ferrous sulfate (FeSO₄). BA was administered orally to evaluate its potential neuroprotective effects.

Results

Our findings demonstrated that BA administration significantly reversed behavioral deficits and mitigated molecular, immunohistopathological, and biochemical abnormalities in LPS + FeSO₄-induced PD model. Notably, BA treatment restored levels of tyrosine hydroxylase (TH) and reduced alpha-synuclein (α-syn) accumulation, both of which were significantly altered in this model. These neuroprotective effects were accompanied by a reduction in oxidative stress, ferroptosis, and apoptosis biomarkers implicated in neurodegeneration.

Summary

These results collectively suggested that α-syn aggregation, ferroptosis, and apoptotic cell death are the critical contributors to PD pathology and highlighted Betulinic acid as a promising therapeutic candidate for combating neurodegeneration in PD. These findings may open new avenues for developing pharmacological agents targeting the complex mechanisms of PD.