Punicalagin's Protective Effects on Parkinson's Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway

Hoda A Salem; Karema Abu-Elfotuh; Sharifa Alzahrani; Nermin I Rizk; Howaida S Ali; Nehal Elsherbiny; Alhanouf Aljohani; Ahmed M E Hamdan; Panneerselvam Chellasamy; Nada S Abdou; Ayah M H Gowifel; Alshaymaa Darwish; Osama Mohamed Ibrahim; Zakaria Y Abd Elmageed

doi:10.3390/pharmaceutics15102420

Punicalagin's Protective Effects on Parkinson's Progression in Socially Isolated and Socialized Rats: Insights into Multifaceted Pathway

Pharmaceutics. 2023 Oct 4;15(10):2420. doi: 10.3390/pharmaceutics15102420.

Authors

Hoda A Salem^{1

2}, Karema Abu-Elfotuh², Sharifa Alzahrani³, Nermin I Rizk⁴, Howaida S Ali^{3

5}, Nehal Elsherbiny^{6

7}, Alhanouf Aljohani⁸, Ahmed M E Hamdan¹, Panneerselvam Chellasamy⁹, Nada S Abdou¹⁰, Ayah M H Gowifel¹¹, Alshaymaa Darwish¹², Osama Mohamed Ibrahim¹³, Zakaria Y Abd Elmageed¹⁴

Affiliations

¹ Department of Pharmacy Practice, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
² Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
³ Department of Pharmacology, Faculty of Medicine, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁴ Medical Physiology Department, Faculty of Medicine, Menoufia University, Menouf 32952, Egypt.
⁵ Department of Pharmacology, Faculty of Medicine, Assiut University, Assiut 71515, Egypt.
⁶ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁷ Department of Biochemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
⁸ Faculty of Pharmacy, University of Tabuk, Tabuk 71491, Saudi Arabia.
⁹ Department of Biology, Faculty of Science, Tabuk University, Tabuk 71491, Saudi Arabia.
¹⁰ Faculty of Medicine, Misr University for Science and Technology (MUST), Giza 11556, Egypt.
¹¹ Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information (MTI), Cairo 11571, Egypt.
¹² Biochemistry Department, Faculty of Pharmacy, Sohag University, Sohag 82524, Egypt.
¹³ Clinical Pharmacy Department, Faculty of Pharmacy, University of Tanta, Tanta 31527, Egypt.
¹⁴ Department of Pharmacology, Edward Via College of Osteopathic Medicine, University of Louisiana at Monroe, Monroe, LA 71203, USA.

Abstract

Parkinson's disease (PD) is a gradual deterioration of dopaminergic neurons, leading to motor impairments. Social isolation (SI), a recognized stressor, has recently gained attention as a potential influencing factor in the progress of neurodegenerative illnesses. We aimed to investigate the intricate relationship between SI and PD progression, both independently and in the presence of manganese chloride (MnCl₂), while evaluating the punicalagin (PUN) therapeutic effects, a natural compound established for its cytoprotective, anti-inflammatory, and anti-apoptotic activities. In this five-week experiment, seven groups of male albino rats were organized: G1 (normal control), G2 (SI), G3 (MnCl₂), G4 (SI + MnCl₂), G5 (SI + PUN), G6 (MnCl₂ + PUN), and G7 (SI + PUN + MnCl₂). The results revealed significant changes in behavior, biochemistry, and histopathology in rats exposed to SI and/or MnCl₂, with the most pronounced effects detected in the SI rats concurrently exposed to MnCl₂. These effects were associated with augmented oxidative stress biomarkers and reduced antioxidant activity of the Nrf2/HO-1 pathway. Additionally, inflammatory pathways (HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1 and JAK-2/STAT-3) were upregulated, while dysregulation of signaling pathways (PI3K/AKT/GSK-3β/CREB), sustained endoplasmic reticulum stress by activation PERK/CHOP/Bcl-2, and impaired autophagy (AMPK/SIRT-1/Beclin-1 axis) were observed. Apoptosis induction and a decrease in monoamine levels were also noted. Remarkably, treatment with PUN effectively alleviated behaviour, histopathological changes, and biochemical alterations induced by SI and/or MnCl₂. These findings emphasize the role of SI in PD progress and propose PUN as a potential therapeutic intervention to mitigate PD. PUN's mechanisms of action involve modulation of pathways such as HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3/Caspase-1, JAK-2/STAT-3, PI3K/AKT/GSK-3β/CREB, AMPK/SIRT-1, Nrf2/HO-1, and PERK/CHOP/Bcl-2.

Keywords: AMPK/SIRT-1; HMGB1/RAGE/TLR4/NF-ᴋB/NLRP3; PI3K/AKT/GSK-3β/CREB; PUN; Parkinson’s disease; social isolation.

Grants and funding

0050-1443-S/University of Tabuk