Rajan Goel

APD668, a G protein-coupled receptor 119 agonist improves fat tolerance and attenuates fatty liver in high-trans fat diet induced steatohepatitis model in C57BL/6 mice

ABSTRACT G‐protein coupled receptor 119 (GPR119) receptor is a rhodopsin‐like, class A G&agr;s‐coupled receptor, predominantly expressed in pancreatic islet cells and intestinal entero‐endocrine cells. GPR119 has been emerged as a novel therapeutic target for the treatment of dyslipidemia in type 2 diabetes. In this study, we investigated the effect of APD668, a GPR119 agonist alone and in combination with linagliptin, a DPPIV inhibitor on oral fat tolerance test. Our findings demonstrate that APD668, a GPR119 agonist inhibits the intestinal triglyceride absorption after acute fat load in mice. Single dose administration of APD668 increases incretin secretion and enhances total PYY levels in presence of fat load in mice. We found that, the anti‐dyslipidemic action of APD668 was reversed in presence of exendin‐3 in oral fat tolerance test. In addition, our results showed that exendin‐3 (9−39) failed to block the effect of APD668 on gastric emptying indicating that gastric emptying effects of APD668 are indeed mediated through GPR119 receptor dependent mechanism. Combined administration of APD668 and linagliptin significantly increased plasma active GLP‐1 levels in‐vivo and showed improvement in fat tolerance. However, APD668 failed to show anti‐dyslipidemic activity in tyloxapol‐induced hyperlipidemia in mice. Furthermore, we investigated the chronic effects of APD668 on hepatic steatosis in high trans‐fat diet fed steatohepatitis model in mice. Oral administration of APD668 in HTF diet fed mice ameliorated hepatic endpoints such as plasma ALT, AST, liver weight and steatosis. These findings suggest that GPR119 agonists may represent a promising therapeutic strategy for the treatment of dyslipidemia and non‐alcoholic steatohepatitis.

Effect of D-Ala2GIP, a stable GIP receptor agonist on MPTP-induced neuronal impairments in mice

Abstract The aim of the present study was to evaluate the ability of D‐Ala2GIP, a gastric inhibitory polypeptide (GIP) receptor agonist, to attenuate the behavioral phenotype of Parkinsons disease caused by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) administration in mice. In the behavioral studies, MPTP administration led to spontaneous locomotor activity deficits, impaired rotarod performance, akinesia, muscular rigidity and increased tremor amplitude, which was attenuated by pretreatment with D‐Ala2GIP (50–100 nmol/kg, i.p.). This acute neuroprotective response by D‐Ala2GIP was found to be blocked by a selective GIP receptor antagonist, (Pro3)GIP (50 nmol/kg, i.p.), indicating that the observed effects are mediated through GIP receptor mediated signaling pathway. Biochemical studies revealed that D‐Ala2GIP reduced the brain malondialdehyde levels and enhanced the brain glutathione levels, thereby mitigating the MPTP‐induced oxidative stress. MPTP administration resulted in reduction of the striatal concentration of dopamine and its metabolites, homovanillic acid (HVA) and 3, 4‐Dihydroxyphenylacetic acid (DOPAC). Pretreatment with D‐Ala2GIP attenuated the loss of striatal dopamine levels without affecting the normal dopamine catabolism. Thus, the observed effects in the MPTP‐induced Parkinsonism model could be in part attributable to the antioxidant properties of D‐Ala2GIP and enhanced turnover of dopamine in the nigrostriatal pathways in mouse brain. These findings together suggest that GIP receptor could be a therapeutic target in the management of symptoms of Parkinsons disease.

Bilateral quinolinic acid-induced lipid peroxidation, decreased striatal monoamine levels and neurobehavioral deficits are ameliorated by GIP receptor agonist D-Ala2GIP in rat model of Huntington's disease

ABSTRACT Huntingtons disease (HD) is an inherited complex progressive neurodegenerative disorder with an established etiopathology linked to neuronal oxidative stress and corticostriatal excitotoxicity. Present study explores the effects of glucose‐dependent insulinotropic polypeptide (GIP) receptor agonist on the neurobehavioral sequelae of quinolinic acid‐induced phenotype of Huntingtons disease in rats. Bilateral administration of quinolinic acid (300nmol/4&mgr;l) to the rat striatum led to characteristic deficits in, locomotor activity, motor coordination, neuromuscular coordination and short‐term episodic memory. Therapeutic treatment for 14 days with a stable and brain penetrating GIP receptor agonist, D‐Ala2GIP (100nmol/kg, i.p.), attenuated the neurobehavioral deficits due to quinolinic acid (QA) administration. Protective actions of D‐Ala2GIP were sensitive to blockade with a GIP receptor antagonist, (Pro3)GIP (50nmol/kg, i.p.), indicating specific involvement of GIP receptor signaling pathway. Stimulation of GIP receptor with D‐Ala2GIP attenuated lipid peroxidation, evidenced by reduced levels of brain malondialdehyde (MDA), and restoration of reduced glutathione (GSH) levels in brain. Quinolinic acid administration led to significant loss of striatal monoamines, e.g., norepinephrine, epinephrine, serotonin, dopamine, and metabolites, 3,4‐Dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5‐Hydroxyindoleacetic acid (5‐HIAA). D‐Ala2GIP attenuated the QA‐induced depletion of striatal monoamines, without affecting the monoamine degradation pathways. Thus, observed effects with D‐Ala2GIP in the QA‐induced Huntingtons disease model could be attributable to reduction in lipid peroxidation, restoration of endogenous antioxidants and decreased striatal monoamine levels. These findings together suggest that stimulation of GIP receptor signaling pathway in brain could be a potential therapeutic strategy in the symptomatic management of Huntingtons disease.

Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in mice fed on a high trans-fat diet

Non-Alcoholic SteatoHepatitis (NASH) is the more severe form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, hepatocyte injury with or without fibrosis. Recently, GPR119 receptor has emerged as a novel therapeutic target for the treatment of dyslipidemia and non-alcoholic steatohepatitis. In the present study, we investigated the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor on the progression of steatohepatitis in mice fed on a high trans-fat diet. In this study, monotherapy with either APD668 or linagliptin caused a reduction in the levels of ALT, AST, glucose, cholesterol and epididymal fat mass but the effect was more pronounced upon treatment with combination of both drugs. On the other hand, combined treatment of APD668 with linagliptin demonstrated a non-significant additive effect in reduction of hepatic triglyceride (-78%) and cholesterol (-56%) compared to monotherapy groups. Moreover, co-administration of APD668 and linagliptin resulted in enhanced levels of active GLP-1 with additional benefit of significant synergistic decrease in body weight gain (-19%) in mice. We speculated that the enhanced effect observed with the combination treatment could be due to either 1) direct activation of GPR119 receptors present in liver and intestine or 2) enhanced active GLP-1 levels or 3) decreased degradation of GLP-1 in-vivo through DPPIV inhibition. Therefore, these findings clearly suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of non-alcoholic steatohepatitis.

Targeting glucose-dependent insulinotropic polypeptide receptor for neurodegenerative disorders

ABSTRACT Introduction: Incretin hormones, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1) exert pleiotropic effects on endocrine pancreas and nervous system. Expression of GIP and GIP receptor (GIPR) in neurons, their roles in neurogenesis, synaptic plasticity, neurotransmission, and neuromodulation uniquely position GIPR for therapeutic applications in neurodegenerative disorders. GIP analogs acting as GIPR agonists attenuate neurobehavioral and neuropathological sequelae of neurodegenerative disorders in preclinical models, e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD), and cerebrovascular disorders. Modulation of GIPR signaling offers an unprecedented approach for disease modification by arresting neuronal viability decline, enabling neuronal regeneration, and reducing neuroinflammation. Growth-promoting effects of GIP signaling and broad-based neuroprotection highlight the therapeutic potential of GIPR agonists. Areas covered: This review focuses on the role of GIPR-mediated signaling in the central nervous system in neurophysiological and neuropathological conditions. In context of neurodegeneration, the article summarizes potential of targeting GIPR signaling for neurodegenerative conditions such as AD, PD, traumatic brain injury, and cerebrovascular disorders. Expert opinion: GIPR represents a validated therapeutic target for neurodegenerative disorders. GIPR agonists impart symptomatic improvements, slowed neurodegeneration, and enhanced neuronal regenerative capacity in preclinical models. Modulation of GIPR signaling is potentially a viable therapeutic approach for disease modification in neurodegenerative disorders.