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7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer’s disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance

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Abstract

Rationale

Intracerebroventricular (ICV) streptozotocin (STZ) mimics sporadic Alzheimer’s disease (SAD) characterized by tau pathology and neurodegeneration arising from oxidative stress, mitochondrial dysfunction, and insulin resistance. 7,8-Dihydroxyflavone (7,8-DHF) is a flavonoid having antioxidant property interlinked with mitochondrial functioning and insulin actions.

Objectives

To evaluate the neuroprotective and cognitive enhancement properties of 7,8-DHF in an ICV-STZ rat model of SAD.

Methods

ICV-STZ (3 mg/kg) was injected into male Wistar rats. Cognitive functions were evaluated by Morris water maze (MWM) and novel object recognition (NOR). 7,8-DHF (5 mg/kg, 10 mg/kg, and 20 mg/kg) and rivastigmine (2 mg/kg) were given orally for 21 days. Reduced glutathione (GSH), catalase, superoxide dismutase (SOD), glutathione peroxidase (GPX), lipid peroxidation (LPO), protein carbonylation (PCO), and nitrite assays were performed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were determined. ELISA for the insulin-degrading enzyme (IDE) and p-tau was done. Histopathology was investigated by hematoxylin and eosin staining.

Results

7,8-DHF treatment attenuated ICV-STZ-induced cognitive deficit in MWM and NOR. Moreover, in the cortex and hippocampus regions of the brain, GSH, catalase, SOD, GPX, LPO, PCO, and nitrite levels were reversed. Mitochondrial enzyme complex I, II, III, and IV, and acetylcholinesterase (AchE) activities were also normalized. IDE and p-tau protein were found to be significantly altered. 7,8-DHF provided protection from neuronal cell death examined in histopathology.

Conclusions

Conclusively, 7,8-DHF was found to be neuroprotective in the ICV-STZ rat model by ameliorating oxidative stress, mitochondrial dysfunction, and insulin resistance, thereby improving cognitive functions evident with the behavioral results.

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Acknowledgments

We would like to thank and acknowledge UIPS, Panjab University, and University Grants Commission (UGC), New Delhi-India for providing the opportunity and grant for the research work. The letter-number for the fellowship grant is F1-17.1/2015-16/MANF-2015-17-BIH-72699.

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  1. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, India

    Ansab Akhtar, Jatinder Dhaliwal & Sangeeta Pilkhwal Sah

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  1. Ansab Akhtar
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Correspondence to Sangeeta Pilkhwal Sah.

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Highlights

• ICV-STZ caused cognitive impairment in rat resembling sporadic Alzheimer’s disease.

• ICV-STZ-induced cognitive impairment was revealed in MWM and NOR.

• Oxidative stress, mitochondrial dysfunction, and insulin resistance were reported.

• 7,8-DHF reversed oxidative stress, mitochondrial dysfunction, and insulin resistance.

• 7,8-DHF halted tau pathology and neurodegeneration.

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Akhtar, A., Dhaliwal, J. & Sah, S.P. 7,8-Dihydroxyflavone improves cognitive functions in ICV-STZ rat model of sporadic Alzheimer’s disease by reversing oxidative stress, mitochondrial dysfunction, and insulin resistance. Psychopharmacology 238, 1991–2009 (2021). https://doi.org/10.1007/s00213-021-05826-7

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  • DOI: https://doi.org/10.1007/s00213-021-05826-7

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