Apigenin reverses behavioural impairments and cognitive decline in kindled mice via CREB-BDNF upregulation in the hippocampus

Abstract

Objectives: Apigenin is the most common bioflavonoid known to be biologically active after systemic administration and show multiple pharmacological effects. The present study was designed to explore the role of apigenin in pentylenetetrazole (PTZ) kindling associated cognitive and behavioural impairments in the mouse model. Methods: The animals were kindled by injecting a sub-convulsive dose of PTZ (35 mg/kg) on every alternate day, followed by 20 days treatment with apigenin at two different doses (10 and 20 mg/kg). Seizure severity was assessed on every 5th, 10th, 15th, and 20th day during apigenin treatment after a PTZ injection, followed by analysis of cognitive and behavioural functions. Results: Apigenin treatment displayed insignificant effect on seizure severity in kindled mice at both the tested doses, in comparison to control. However, the treatment showed marked increase in per cent spontaneous alterations and decline in the anxiety index in T-maze and elevated plus maze tests, respectively. Apigenin-treated groups showed significant decrease in immobility period in both forced swim and tail suspension tests, without any change in the total locomotor activity in the open field test. Furthermore, increase in the hippocampus protein expression of brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB), and phosphorylated CREB, with increased serotonin level were also observed in the treated animals. Discussion: The results of the present study showed that apigenin treatment prevents cognitive deficit and reverses behaviour impairments, without altering seizures severity in kindled mice. The observed effects can be attributed to CREB-BDNF upregulation in the hippocampus.

Keywords:

• 4′,5,7-Trihydroxyflavone
• cAMP response element binding protein
• Hippocampus
• Neurotrophic factors
• Pentylenetetrazol
• Serotonin
• Spatial learning

Acknowledgements

The authors are highly grateful to the Director, CSIR-Institute of Himalayan Bioresource Technology, Palampur for constant encouragement and providing the necessary infrastructural facilities. The CSIR-IHBT communication number of the manuscript is 4200.

Disclaimer statements

Contributors PS performed the animal experimentation, behaviour analysis, HPLC studies and manuscript writing. SS carried out protein expression studies. DS planned and supervised the study, analyzed the data and contributed in manuscript writing and editing.

Funding The financial support for the work was provided by the CSIR, New Delhi under the project MLP-0039.

Conflicts of interest None.

Ethics approval The experimental protocol was duly approved by the Institutional Animal Ethics Committee in its meeting dated 5^th January 2016.