Dopamine receptor activation mitigates mitochondrial dysfunction and oxidative stress to enhance dopaminergic neurogenesis in 6-OHDA lesioned rats: A role of Wnt signalling.

Dopamine receptor activation mitigates mitochondrial dysfunction and oxidative stress to enhance dopaminergic neurogenesis in 6-OHDA lesioned rats: A role of Wnt signalling.

Publication date: May 09, 2019

Nigral dopaminergic (DAergic) cell degeneration and depletion of dopamine neurotransmitter in the midbrain are cardinal features of Parkinson’s disease (PD). Dopamine system regulates different aspects of behavioural phenotypes such as motor control, reward, anxiety and depression via acting on dopamine receptors (D1-D5). Recent studies have shown the potential effect of dopamine on modulation of neurogenesis, a process of newborn neuron formation from neural stem cells (NSCs). Reduced proliferative capacity of NSCs and net neurogenesis has been reported in subventricular zone, olfactory bulb and hippocampus of patients with PD. However, the molecular and cellular mechanism of dopamine mediated modulation of DAergic neurogenesis is not defined. In this study, we attempted to investigate the molecular mechanism of dopamine receptors mediated control of DAergic neurogenesis and whether it affects mitochondrial biogenesis in 6-hydroxydopamine (6-OHDA) induced rat model of PD-like phenotypes. Unilateral administration of 6-OHDA into medial forebrain bundle potentially reduced tyrosine hydroxylase immunoreactivity, dopamine content in substantia nigra pars compacta (SNpc) and striatum region and impaired motor functions in adult rats. We found decreased D1 receptor expression, mitochondrial biogenesis, mitochondrial functions and DAergic differentiation associated with down-regulation of Wnt/β-catenin signalling in SNpc of 6-OHDA lesioned rats. Pharmacological stimulation of D1 receptor enhanced mitochondrial biogenesis, mitochondrial functions and DAergic neurogenesis that lead to improved motor functions in 6-OHDA lesioned rats. D1 agonist induced effects were attenuated following administration of D1 antagonist, whereas shRNA mediated knockdown of Axin-2, a negative regulator of Wnt signalling significantly abolished D1 antagonist induced impairment in mitochondrial biogenesis and DAergic neurogenesis in 6-OHDA lesioned rats. Our results suggest that dopamine receptor regulates DAergic neurogenesis and mitochondrial functions by activation of Wnt/β-catenin signalling in rat model of PD-like phenotypes.

Mishra, A., Singh, S., , Tiwari, Chaturvedi, S., Wahajuddin, M., and Shukla, S. Dopamine receptor activation mitigates mitochondrial dysfunction and oxidative stress to enhance dopaminergic neurogenesis in 6-OHDA lesioned rats: A role of Wnt signalling. 20750. 2019 Neurochem Int.

Concepts Keywords
Agonist Oxidopamine
Antagonist Adult neurogenesis
Anxiety Wnt signaling pathway
Axin Substantia nigra
Cardinal Amphetamine
Depression Catecholamines
Dopamine Dopamine receptors
Dopamine Receptor Branches of biology
Dopaminergic Neuroscience
Hippocampus Dysfunction
Immunoreactivity
Midbrain
Mitochondrial
Modulation
Motor Control
Neurogenesis
Neuron
Neurotransmitter
Olfactory Bulb
Oxidative Stress
Parkinson
Phenotypes
Receptor
Receptors
ShRNA
Striatum
Subventricular Zone
Tyrosine Hydroxylase
Wnt Signalling

Semantics

Type Source Name
gene UNIPROT AXIN1
drug DRUGBANK L-Tyrosine
pathway BSID Mitochondrial biogenesis
gene UNIPROT ELK3
gene UNIPROT EPHB1
gene UNIPROT SLC6A2
pathway BSID Dopamine receptors
disease MESH depression
disease DOID anxiety
disease MESH anxiety
gene UNIPROT CARD8
pathway BSID Dopaminergic Neurogenesis
pathway BSID Oxidative Stress
disease MESH oxidative stress
drug DRUGBANK Dopamine

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