title: 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 Parkinson's 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 Parkinson's disease.
authors.affiliation: Department of Pharmacology, Novel Drug Discovery and Development, Lupin Limited (Research Park), Pune 412115, Maharashtra, India. Electronic address: mahipverma@lupin.com.
authors.forename: Mahip K
authors.initials: MK
authors.lastname: Verma
authors.affiliation: Department of Pharmacology, Novel Drug Discovery and Development, Lupin Limited (Research Park), Pune 412115, Maharashtra, India.
authors.forename: Rajan
authors.initials: R
authors.lastname: Goel
authors.affiliation: Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576104, Karnataka, India.
authors.forename: Krishnadas
authors.initials: K
authors.lastname: Nandakumar
authors.affiliation: Department of Pharmacology, Novel Drug Discovery and Development, Lupin Limited (Research Park), Pune 412115, Maharashtra, India.
authors.forename: Kumar V S
authors.initials: KVS
authors.lastname: Nemmani
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology*; D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D004298:Dopamine / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D006719:Homovanillic Acid / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D014202:Tremor / Q000188:drug therapy
chemical_list: D018696:Neuroprotective Agents; D011964:Receptors, Gastrointestinal Hormone; D015102:3,4-Dihydroxyphenylacetic Acid; D008315:Malondialdehyde; D005749:Gastric Inhibitory Polypeptide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; C041086:gastric inhibitory polypeptide receptor; D005978:Glutathione; D004298:Dopamine; D006719:Homovanillic Acid
keywords: (Pro(3))GIP; D-Ala(2)GIP; Neuroprotection; Parkinson's disease; Redox