Dabigatran Combined With Benztropine Ameliorates Cobalt Chloride-Induced Parkinsonism in Rats, Restores Protease-Activated Receptor 1 (PAR1), and Mitigates Oxidative Stress.

BACKGROUND

The presumed implication of thromboembolic and oxidative stress pathways in parkinsonism guided the current research toward the exploration of the anticoagulant dabigatran etexilate (DE) as a thrombin inhibitor in the cobalt chloride (CoCl)-induced parkinsonism (CIP) model, a model of significance to industrial toxins-related health issues.

METHODS

Oral CoCl (12.5 mg/kg) was administered daily for 60 days, with the introduction of benztropine mesylate (BM) (10 mg/kg) and/or DE (3 mg/kg) on day 31. Rearing, postural instability, and pasta handling were evaluated, followed by histopathologic examination of the substantia nigra (SN) and striatum (STR). The expressions of brain dopamine receptor 2 ( ), adenosinereceptor 1 (A) and 2A (A), and protease-activated receptor 1 (PAR1), as well as the brain levels of dopamine (DA), endothelin 1 (ET1), malondialdehyde (MDA), and glutathione (GSH), were assessed.

RESULTS

BM+DE restored the number of rears to the control level, compared to being reduced in the CIP model. BM+DE restored the first, second, third, and average displacement distances to the control level, compared to being reduced in the CIP model. BM+DE was superior to either BM or DE in restoring the time to finish eating pasta and the number of adjustments of forepaws while eating to control levels after being affected in the CIP model. BM+DE restored DA to the control level and was superior to DE in restoring D to the control level. BM+DE was superior to BM in restoring Aand A  increasing A/Abeyond the control levelBM+DE was superior to BM in restoring PAR1 and ET1 to control levels. BM+DE was superior to BM in restoring MDA to the control level and was superior to both BM and DE in increasing GSH beyond the control level. BM+DE exhibited the highest percentage of preserved neurons in SN, which was negatively correlated with MDA.

CONCLUSION

BM+DE offers a therapeutic potential for parkinsonism triggered by chronic exposure to CoCl. The implication of thrombin-related factors and oxidative stress in the modulation of the dopaminergic-adenosinergic crosstalk is plausible.