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The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson's Disease.

ABSTRACT: The proton-activated G protein-coupled receptor (GPCR) 4 (GPR4) is constitutively active at physiological pH, and GPR4 knockout protected dopaminergic neurons from caspase-dependent mitochondria-associated apoptosis. This study explored the role of GPR4 in a 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-treated mouse model of Parkinson's disease (PD). In mice, subchronic MPTP administration causes oxidative stress-induced apoptosis in the dopaminergic neurons of the substantia nigra pars compacta (SNpc), resulting in motor deficits. NE52-QQ57, a selective GPR4 antagonist, reduced dopaminergic neuronal loss in MPTP-treated mice, improving motor and memory functions. MPTP and NE52-QQ57 co-treatment in mice significantly decreased pro-apoptotic marker Bax protein levels and increased anti-apoptotic marker Bcl-2 protein levels in the SNpc and striatum. MPTP-induced caspase 3 activation and poly (ADP-ribose) polymerase (PARP) cleavage significantly decreased in the SNpc and striatum of mice co-treated with NE52-QQ57. MPTP and NE52-QQ57 co-treatment significantly increased tyrosine hydroxylase (TH)-positive cell numbers in the SNpc and striatum compared with MPTP alone. NE52-QQ57 and MPTP co-treatment improved rotarod and pole test-assessed motor performance and improved Y-maze test-assessed spatial memory. Our findings suggest GPR4 may represent a potential therapeutic target for PD, and GPR4 activation is involved in caspase-mediated neuronal apoptosis in the SNpc and striatum of MPTP-treated mice.

SUBMITTER: Haque ME

PROVIDER: S-EPMC8125349 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The gut hormone ghrelin is widely beneficial in many disease states. However, ghrelin exists in two distinctive isoforms, each with its own metabolic profile. In Parkinson's Disease (PD) acylated ghrelin administration is neuroprotective, however, the role of des-acylated ghrelin remains unknown. In this study, we wanted to identify the relative contribution each isoform plays using the MPTP model of PD. Chronic administration of acylated ghrelin in mice lacking both isoforms of ghrelin (Ghrelin KO) attenuated the MPTP-induced loss on tyrosine hydroxylase (TH) neuronal number and volume and TH protein expression in the nigrostriatal pathway. Moreover, acylated ghrelin reduced the increase in glial fibrillary acidic protein and Ionized calcium binding adaptor molecule 1 microglia in the substantia nigra. However, injection of acylated ghrelin also elevated plasma des-acylated ghrelin, indicating in vivo deacetylation. Next, we chronically administered des-acylated ghrelin to Ghrelin KO mice and observed no neuroprotective effects in terms of TH cell number, TH protein expression, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 cell number. The lack of a protective effect was mirrored in ghrelin-O-acyltransferase KO mice, which lack the ability to acylate ghrelin and consequently these mice have chronically increased plasma des-acyl ghrelin. Plasma corticosterone was elevated in ghrelin-O-acyltransferase KO mice and with des-acylated ghrelin administration. Overall, our studies suggest that acylated ghrelin is the isoform responsible for in vivo neuroprotection and that pharmacological approaches preventing plasma conversion from acyl ghrelin to des-acyl ghrelin may have clinical efficacy to help slow or prevent the debilitating effects of PD. Ghrelin exists in the plasma as acyl and des-acyl ghrelin. We determined the form responsible for in vivo neuroprotection in a mouse model of Parkinson's disease. Although exogenous acyl ghrelin is deacylated in situ to des-acyl, only acyl ghrelin was neuroprotective by attenuating dopamine cell loss and glial activation. Acyl ghrelin is a therapeutic option to reduce Parkinson's Disease progression. Cover Image for this issue: doi: 10.1111/jnc.13316.

Project description:Parkinson's disease (PD) is a common degenerative disease of the central nervous system. Although some drugs can alleviate the progress of PD, their long-term use will lead to complications, so it is still necessary to find new drugs to delay or cure PD effectively. In view of the difficulty in developing new drugs, it is imperative to discover new functions of existing compounds that could be used to treat PD. In this study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce PD symptoms in a mouse model. Subsequently, these mice were treated with the antibiotic ceftriaxone. Ceftriaxone alleviated the behavioural and neuropathological changes induced by MPTP, downregulated the expression of glial fibrillary acidic protein (GFAP) and ionised calcium-binding adapter molecule 1 (Iba1) as markers of astroglia and microglia, respectively, and reduced the expression of neuroinflammation-related Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), and phosphorylated nuclear factor kappa-B (p-NF-κB)/NF-κB in the brain of PD mice. In addition, ceftriaxone reduced the abundance of pathogenic bacteria of the genus Proteus and increased the abundance of probiotic Akkermansia. Finally, ceftriaxone treatment increased the expression of the tight junction proteins zona occludens-1(ZO-1) and occludin in the colon, decreased the expression of the inflammation-related proteins TLR4, MyD88, and NF-κB in the colon, and decreased the serum concentration of the proinflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumour necrosis factor-α (TNF-α). These results indicate that ceftriaxone had a neuroprotective effect on MPTP-induced PD mice, and its neuroprotective effect could be through regulating inflammation and intestinal microbiota. While we showed that ceftriaxone exerts a neuroprotective effect in an MPTP-induced PD mouse model, our findings are limited to the short-term effects of ceftriaxone. Additional work using transgenic mice is required to determine the long-term effects of ceftriaxone. In addition, the dose and frequency of ceftriaxone use should be evaluated.

Project description:Grape pomaces have recently received great attention for their richness in polyphenols, compounds known to exert anti-inflammatory and antioxidant effects. These pomaces, however, have low brain bioavailability when administered orally due to their extensive degradation in the gastrointestinal tract. To overcome this problem, Nasco pomace extract was incorporated into a novel nanovesicle system called nutriosomes, composed of phospholipids (S75) and water-soluble maltodextrin (Nutriose® FM06). Nutriosomes were small, homogeneously dispersed, had negative zeta potential, and were biocompatible with intestinal epithelial cells (Caco-2). Nasco pomace extract resulted rich in antioxidant polyphenols (gallic acid, catechin, epicatechin, procyanidin B2, and quercetin). To investigate the neuroprotective effect of Nasco pomace in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), Nasco nutriosomes or Nasco suspension was administered intragastrically and their neuroprotective effects were evaluated. Degeneration of nigro-striatal dopaminergic neurons induced by subacute MPTP treatment, the pathological hallmark of PD, was assessed through immunohistochemical evaluation of tyrosine hydroxylase (TH) in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc), and the dopamine transporter (DAT) in CPu. Immunohistochemical analysis revealed that Nasco nutriosomes significantly prevented the reduction in TH- and DAT-positive fibres in CPu, and the number of TH-positive cells in SNc following subacute MPTP treatment, while Nasco suspension counteracted MPTP toxicity exclusively in SNc. Overall, these results highlight the therapeutic effects of Nasco pomace extract when administered in a nutriosome formulation in the subacute MPTP mouse model of PD and validate the effectiveness of the nutriosome preparation over suspension as an innovative nano-drug delivery system for in vivo administration.

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The Neuroprotective Effects of GPR4 Inhibition through the Attenuation of Caspase Mediated Apoptotic Cell Death in an MPTP Induced Mouse Model of Parkinson's Disease.

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