Oleanolic acid-based therapeutics ameliorate rotenone-induced motor and depressive behaviors in parkinsonian male mice via controlling neuroinflammation and activating Nrf2-BDNF-dopaminergic signaling pathways

Abstract

Parkinson’s disease (PD) is often accompanied by depression, which may appear before motor signs. Oleanolic acid (OA), a pentacyclic triterpenoid substance, have many pharmacological properties. However, its efficacy in treating PD-related chronic unpredictable stress (CUS) is unknown. Our study used behavioral, biochemical, and immunohistochemical techniques to assess how OA affected PDrelated CUS. Rotenone (1 mg/kg i.p. for first 21 days) was used to induce Parkinsonism, and modest psychological & environmental stresses generated CUS (from day 22 to day 43) in animals. The study included daily i.p.administration of OA (5, 10, and 20 mg/kg) from day 1 to day 57 in male swiss albino mice. Animals were evaluated for behavioral, biochemical parameters, neurotransmitters, and immunohistochemical expression following the treatment. Results of the study revealed that treatment with OA at all doses alleviated the core symptoms of CUS linked to PD and improved motor and non-motor function. OA therapy significantly lowered IL-1β, TNF-α (p < 0.01, < 0.01, < 0.001), IL-6 (p < 0.05, < 0.01, < 0.001), oxidative stress (p < 0.05, < 0.01, < 0.01), and elevated norepinephrine (p < 0.05, < 0.01, < 0.01), dopamine, and serotonin (p < 0.05, < 0.01, < 0.001) levels. Moreover, OA therapy substantially reduced α-synuclein (p < 0.05, < 0.01, < 0.01) aggregation and increased BDNF (p < 0.05, < 0.01, < 0.001) & Nrf-2 (p < 0.05, < 0.01, < 0.01) levels, which boosts neuronal dopamine survival. The study’s findings indicated that OA ameliorates depressive-like behavior persuaded by CUS in PD, decreases neuroinflammation, and improves neurotransmitter concentration via activating Nrf2-BDNF-dopaminergic pathway.

KEY POINTS

• Oleanolic acid reversed the CUS-induced depressive behaviors in Parkinson’s disease

• Oleanolic acid alleviated oxidative stress, neuroinflammation, and improved brain neurotransmitter concentration

• Oleanolic acid reduced the α-synuclein aggregation and activated Nrf2-BDNF-dopaminergic signaling pathways to ameliorate motor and depressive behaviors in parkinsonian mice

Keywords:

• Oleanolic acid
• chronic unpredictable stress
• parkinson’s disease
• male swiss albino mice
• rotenone
• depression
• α-synuclein
• nrf-2
• BDNF

Acknowledgments

The essential resources for authoring this research study were provided by SVKM'S NMIMS (Deemed to be University), Mumbai, India, and the authors appreciate their assistance.

Authors’ contributions

Tanvi Dayanand Pingale completed all laboratory work. Girdhari Lal Gupta’s idea generation, literature search, and correctness review of his study effort. The work was written by both authors and jointly edited.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

No financial assistance is available for current research.