Modulatory Role of Nurr1 Activation and Thrombin Inhibition in the Neuroprotective Effects of Dabigatran Etexilate in Rotenone-Induced Parkinson’s Disease in Rats

Abstract

Recently, it has been shown that both decreased nuclear receptor-related 1 (Nurr1) expression and thrombin accumulation are involved in the degeneration of dopaminergic neurons in Parkinson's disease (PD). The new anticoagulant dabigatran etexilate (DE) is a direct thrombin inhibitor that owns benzimidazole group, which has been proposed to activate Nurr1. In the present study, we examined the neuroprotective effects of DE in rotenone model of PD. Rotenone was injected subcutaneously at a dose of 1.5 mg/kg every other day for 21 days. An oral regimen of DE (15 mg/kg) was started after the 5th rotenone injection following the manifestations of PD. Treatment of PD rats with DE mitigated rotenone-induced neuronal degeneration and restored striatal dopamine level with motor recovery. As well, DE enhanced Nurr1 expression in substantia nigra along with increasing transcriptional activation of Nurr1-controlled genes namely tyrosine hydroxylase, vascular monoamine transporter, glial cell line-derived neurotrophic factor, and its receptor gene c-Ret, which are critical for development and maintenance of dopaminergic neurons. DE also suppressed thrombin accumulation in substantia nigra. Both effects probably contributed to repressing neurotoxic proinflammatory cytokines, which was manifested by decreased level of nuclear factor kappa beta and tumor necrosis factor alpha. In conclusion, the present results suggest that DE could possess significant neuroprotective and regenerative effects in a rotenone-induced PD animal model as consequence of Nurr1 activation and thrombin inhibition.

Hypoxia‐inducible factor 1 alpha and nuclear‐related receptor 1 as targets for neuroprotection by albendazole in a rat rotenone model of Parkinson's disease

“…In this study, rotenone caused a substantial decrease in Nurr1 mRNA expression in the SN with a subsequent decline in TH and VMAT levels and suppression of GDNF/c‐Ret signalling, which contributed to the observed nigral neuronal injury and striatal DA reduction. These results are consistent with other studies that showed a reduction in Nurr1 together with Nurr1‐related genes in PD models . The decrease in Nurr1 expression in PD rats could be due to rotenone‐induced α‐synuclein accumulation, which regulates the degradation of Nurr1 protein .…”

“…Furthermore, our previous work revealed decreased expression of nuclear receptor related 1 (Nurr1) in an animal model of rotenone‐induced PD and this has been suggested to contribute to the degeneration of dopaminergic neurons . Nurr1 is a transcription factor that is related to the nuclear receptor superfamily and is expressed predominantly in the central nervous system, especially in the substantia nigra (SN) .…”

Metal Chelation Therapy and Parkinson’s Disease: A Critical Review on the Thermodynamics of Complex Formation between Relevant Metal Ions and Promising or Established Drugs

“…Creatine [179,180] Cudraflavone B [181] Curcumin [89,117,[182][183][184] Cyanidin [185,186] D-512 [187] D-607 (bipyridyl-D2R/D3R agonist hybrid) [12,188,189] DA-2 (8D) [12,89] DA-3 [12] DA-4 [12] Dabigatran etexilate [190] Dabrafenib [191] (S)-3,4-DCPG [115] Deferasirox [24] Deferricoprogen [192] Delphinidin [160,185,193,194] Demethoxycurcumin [195] Dendropanax morbifera active compound [196] Desferrioxamine (Desferoxamine, Desferal, DFO) [112] (S)-N-(3-(3,6-Dibromo-9H -carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [197] 4,5-O-Dicaffeoyl-1-O-(malic acid methyl ester)-quinic acid derivatives (R1, R2, R3, R4, or R5 = caffeoyl) [198] Dihydromyricetin [199]…”

Effect of the asthma-chronic obstructive pulmonary disease syndrome on the stroke, Parkinson's disease, and dementia: a national cohort study

“…Several studies have reported an association between an increased atherosclerosis-related [ 34 ] inflammation markers [(e.g. TNF-α [ 33 ] and an increased risk of neurodegenerative diseases [ 32 ], including stroke [ 34 ], dementia and PD [ 35 ]. The level of TNF-α increased in the ACOS cohort [ 36 ] and its value is higher than the control groups [ 32 ].…”

“…The aging [ 45 ] and atherosclerosis-related diseases of ACOS cohort are associated with the system inflammation [ 31 ] also. Considering these speculations [ 30 , 35 , 39 ]; aging, hypoxemia [ 16 , 42 ] and system inflammation [ 14 , 31 ] are predisposing factors [ 33 ] for neurodegenerative diseases (e.g. stroke) even without the comorbidities.…”