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Calcitriol Pretreatment Attenuates Glutamate Neurotoxicity by Regulating NMDAR and CYP46A1 Gene Expression in Rats
Negar Khassafi1,2, Zohreh Zahraei1, Zeinab Vahidinia2
1From the Department of Cell and Molecular Biology, Faculty of Chemistry, University of Kashan, Kashan, Iran.
Abstract:
Although the neuroprotective effects of calcitriol have been demonstrated in a variety of neurological diseases, such as stroke, the precise molecular mechanism has yet to be determined. This study aimed to investigate the possible role of calcitriol as a neuroprotective agent via CYP46A1 and glutamate receptors in a middle cerebral artery occlusion (MCAO) animal model. The MCAO technique was performed on adult male Wistar rats to induce focal cerebral ischemia for 1 hour followed by 23 hours of reperfusion. Calcitriol was given for 7 days prior to stroke induction. Sensorimotor functional tests were done 24 hours after ischemia/reperfusion, and infarct volume was estimated by tetrazolium chloride staining of brain sections. Gene expression of NR2A, NR2B, NR3B, and CYP46A1 was evaluated by RT-PCR followed by western blotting for NR3B protein. Our data revealed that calcitriol pretreatment reduced lesion volume and improved ischemic neurobehavioral parameters. Calcitriol therapy altered the expression of glutamate receptor and CYP46A1 genes. A possible molecular mechanism of calcitriol to reduce the severity and complications of ischemia may be through alterations of glutamate receptor and CYP46A1 gene expression.
Insights
Calcitriol (vitamin D) shows neuroprotective effects in stroke models by reducing brain damage and improving function. It influences key genes related to glutamate receptors and CYP46A1, suggesting a molecular pathway for its therapeutic benefits.
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Calcitriol (vitamin D) is known for neuroprotective effects in neurological diseases like stroke.
- The exact molecular mechanisms underlying calcitriol's neuroprotection remain unclear.
- Investigating calcitriol's role in stroke requires understanding its impact on specific molecular targets.
Purpose of the Study:
- To explore calcitriol's neuroprotective potential in a stroke model.
- To investigate the involvement of CYP46A1 and glutamate receptors in calcitriol's mechanism.
- To elucidate the molecular pathways mediating calcitriol's effects on cerebral ischemia.
Main Methods:
- A middle cerebral artery occlusion (MCAO) rat model was used to induce focal cerebral ischemia.
- Calcitriol was administered for 7 days prior to inducing ischemia/reperfusion.
- Neurobehavioral tests, infarct volume assessment, and gene/protein expression analysis (RT-PCR, Western blotting) were performed.
Main Results:
- Calcitriol pretreatment significantly reduced infarct volume and improved sensorimotor function post-ischemia.
- Calcitriol altered the gene expression of glutamate receptors (NR2A, NR2B, NR3B) and CYP46A1.
- Protein expression of NR3B was also modulated by calcitriol treatment.
Conclusions:
- Calcitriol demonstrates significant neuroprotective effects in a rat model of focal cerebral ischemia.
- The study suggests that calcitriol's therapeutic benefits may involve modulating glutamate receptor and CYP46A1 gene expression.
- These findings offer insights into the molecular mechanisms of calcitriol in mitigating stroke severity and complications.
