Neuroprotective effect of taxifolin against aluminum chloride-induced dementia and pathological alterations in the brain of rats: possible involvement of toll-like receptor 4

Abstract

Aluminum (Al) overexposure damages various organ systems, especially the nervous system. Regularly administered aluminum chloride (AlCl₃) to rats causes dementia and pathophysiological alterations linked to Alzheimer’s disease (AD). Taxifolin’s neuroprotective effects against AlCl₃-induced neurotoxicity in vitro and in vivo studies were studied. Taxifolin (0.1, 0.3, 1, 3, and 10 μM) was tested against AlCl₃ (5 mM)-induced neurotoxicity in C6 and SH-SY5Y cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Additionally, neural morphology was examined by confocal microscopy. Additionally, taxifolin’s mode of binding with the co-receptor of toll-like receptor 4 (TLR4), human myeloid differentiation-2 (hMD-2) was investigated. AlCl₃ (25 mg/kg/d, i.p.) was administered to rats for 14 d, and from the eighth day, taxifolin (1, 2, and 5 mg/kg/d, i.p.) was given along with AlCl₃. This study assessed memory impairment using the Morris water maze, plus maze, and pole tests. This study also performed measurement of oxidant (malondialdehyde [MDA] and nitrite), antioxidant (reduced glutathione), and inflammatory (myeloperoxidase [MPO] activity, TLR4 expression) parameters in rats’ brain in addition to histopathology. The docking score for taxifolin with hMD-2 was found to be −4.38 kcal/mol. Taxifolin treatment reduced the neurotoxicity brought on by AlCl₃ in both C6 and SH-SY5Y cells. Treatment with 10 μM taxifolin restored AlCl₃-induced altered cell morphology. AlCl₃ administration caused memory loss, oxidative stress, inflammation (increased MPO activity and TLR4 expression), and brain atrophy. Taxifolin treatment significantly improved the AlCl₃-induced memory impairment. Taxifolin treatment also mitigated the histopathological and neurochemical consequences of repeated AlCl₃ administration in rats. Thus, taxifolin may protect the brain against AD.

Keywords:

• Aluminum chloride
• taxifolin
• toll-like receptor 4
• oxidative stress
• neuroinflammation
• dementia
• Alzheimer’s disease

Acknowledgment

Authors are thankful to Nirma University, Ahmedabad, Gujarat for providing Minor research project grant (Grant no: NU/DRI/MinResPrj/ IP/2019 − 20, Date:21/03/20) to Dr. Bhagawati Saxena and Dr. Nagja Tripathi. The authors also acknowledge the Institute of Pharmacy, Nirma University, Ahmedabad and National Institute of Pharmaceutical Education and Research-Raebareli, Lucknow for supporting the study with research facilities.

Disclosure statement

The authors declare no conflicts of interest.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

Bhagawati Saxena was the recipient of a Minor research project grant from Nirma University, Ahmedabad, Gujarat (Grant no: NU/DRI/MinResPrj/IP/2019 − 20, Date:21/03/20).