Abstract
Parkinson’s disease (PD) is a common neurodegenerative disease, featured by motor deficits and non-motor symptoms such as cognitive impairment, and malfunction of gamma-aminobutyric acid (GABA) mediated inhibitory transmission plays an important role in PD pathogenesis. The ginsenoside Rb1 molecule, a major constituent of the extract from the Ginseng root, has been demonstrated to ameliorate motor deficits and prevent dopaminergic neuron death in PD. However, whether Rb1 can regulate GABAergic transmission in PD-associated deficits and its underlying mechanisms are still unclear. In this study, we explored the effects of Rb1 on the GABAergic synaptic transmission in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We demonstrated that Rb1 can bind with GABAARα1 and increase its expression in the SH-SY5Y cells and in the prefrontal cortex (PFC) of MPTP model in vitro and in vivo. Furthermore, Rb1 can promote prefrontal cortical GABA level and GABAergic transmission in MPTP-treated mice. We also revealed that Rb1 may suppress presynaptic GABABR1 to enhance GABA release and GABAA receptor-mediated inhibitory transmission. In addition, Rb1 attenuated MPTP-induced dysfunctional gait dynamic and cognitive impairment, and this neuroprotective mechanism possibly involved regulating prefrontal cortical GABAergic transmission. Thus, Rb1 may serve as a potential drug candidate for the treatment of PD.
Highlights
Parkinson's disease (PD) is a neurological disorder characterized by the classical motor features of parkinsonism and associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra [1]
When Rb1 was docked in the transmembrane domain (TMD) of GABAARα1, two hydrogen bonds formed with Ile239 and Trp246 sites (Figure 1C and 1D)
GABAergic signaling was downregulated in the PD patients and animal models [3,4,5, 37], and it is urgent to explore the therapeutic strategy targeting GABAergic systems in PD
Summary
Parkinson's disease (PD) is a neurological disorder characterized by the classical motor features of parkinsonism and associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra [1]. Disturbance of the neurotransmitter systems, mainly dopaminergic, glutamatergic, γ-aminobutyric acid www.aging-us.com (GABA)ergic, is a hallmark of PD pathology [2]. GABA is the principal inhibitory transmitter in the mammalian brain, and reduced GABA levels were found in the left basal ganglia of PD patients [3]. The level of somatostatin, a marker for a particular GABAergic interneuronal subpopulation, was found to be significantly decreased in cerebrospinal fluid of PD patients and in GABAergic neurons derived from iPSCs of patients with parkin mutations [4, 5]. GABA activates two classes of its receptors in the central nervous system (CNS); the ionotropic GABAA receptor channel conducts chloride and bicarbonate ions, while the metabotropic GABAB receptor principally activates the G protein-coupled inwardly rectifying potassium (GIRK) channel [7, 8]. GABAA receptors mediate fast inhibitory effects and GABAB receptors mediate slow inhibitory effects [9]
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