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Dopamine receptor inhibition and activation in a PD model

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    This is an Indian study, not a free paper and not telling anything about PBT434. However, it used the same rat model as did the only PBT434 study by Flinkenstein and interestingly they study the effect of DRP-1 and mdivi-1 on the mitochondrial biogenesis, ATP production, mitochondrial membrane potential etc. These are just similar issues I would like to see ATHE to report in different rat models of PD and MSA. Dr. Sinclair could possibly propose even a better study plan but the result of this study is close to what we would like to see as a result of PBT434.


    Behav Brain Res.
    2019 Oct 15:112304. doi: 10.1016/j.bbr.2019.112304. [Epub ahead of print]

    Dopamine D1 receptor agonism induces dynamin related protein-1 inhibition to improve mitochondrial biogenesis and dopaminergic neurogenesis in rat model of Parkinson's disease.

    Author information

    1
    Division of Neuroscience and Ageing biology, CSIR-Central Drug Research Institute, Lucknow (U.P.), India; Academy of Scientific and Innovative Research, New Delhi, India.
    2
    Division of Neuroscience and Ageing biology, CSIR-Central Drug Research Institute, Lucknow (U.P.), India; L4078, Department of Neuroscience, School of Medicine, University of Connecticut (Uconn) Health Center, 263 Farmington Avenue.
    3
    Division of Neuroscience and Ageing biology, CSIR-Central Drug Research Institute, Lucknow (U.P.), India.
    4
    Division of Neuroscience and Ageing biology, CSIR-Central Drug Research Institute, Lucknow (U.P.), India; Academy of Scientific and Innovative Research, New Delhi, India. Electronic address: [email protected]

    Abstract

    Dopamine (DA) neurotransmitter act on dopamine receptors (D1-D5) to regulate motor functions, reward, addiction and cognitive behavior. The depletion of DA in midbrain due to degeneration of nigral dopaminergic (DAergic) neurons leads to Parkinson's disease (PD). DA agonist and levodopa (L-DOPA) are the only therapies used for symptomatic relief in PD. However, the role of DA receptors in PD pathogenesis and how they are associated with mitochondrial functions and DAergic neurogenesis is still not known. Here, we investigated the mechanistic aspect of DA D1 receptor mediated control of DAergic neurogenesis, motor behavior and mitochondrial functions in rat PD model. The pharmacological activation of D1 receptors markedly improved motor deficits, mitochondrial biogenesis, ATP levels, mitochondrial membrane potential and defended nigral DAergic neurons against 6-hydroxydopamine (6-OHDA) induced neurotoxicity in adult rats. However, the D1 agonist mediated effects were abolished following D1 receptor antagonist treatment in 6-OHDA lesioned rats. Interestingly, pharmacological inhibition of dynamin related protein-1 (Drp-1) by Mdivi-1 in D1 antagonist treated PD rats, significantly restored behavioral deficits, mitochondrial functions, mitochondrial biogenesis and increased the number of newborn DAergic neurons in substantia nigra pars compacta (SNpc). Drp-1 inhibition mediated neuroprotective effects in PD rats were associated with increased level of protein kinase-B/Akt and extracellular-signal-regulated kinase (ERK). Taken together, our data suggests that dopamine D1 receptor mediated reduction in mitochondrial fission and enhanced DAergic neurogenesis may involve Drp-1 inhibition which led to improved behavioral recovery in PD rats.

 
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