title: Protective effects of L-pGlu-(2-propyl)-L-His-L-ProNH2, a newer thyrotropin releasing hormone analog in in vitro and in vivo models of cerebral ischemia.
abstract: In the present study, the newly synthesized TRH analog (L-pGlu-(2-propyl)-L-His-l-ProNH(2); NP-647) was evaluated for its effects in in vitro (oxygen glucose deprivation (OGD)-, glutamate- and H(2)O(2)-induced injury in PC-12 cells) and in vivo (transient global ischemia) models of cerebral ischemic injury. PC-12 cells were subjected to oxygen and glucose deprivation for 6h. Exposure of NP-647 was given before and during OGD. In glutamate and H(2)O(2) induced injury, exposure of NP-647 was given 1, 6 and 24h prior to exposure of glutamate and H(2)O(2) exposure. NP-647, per se found to be non-toxic in 1-100μM concentrations. NP-647 showed protection against OGD at the 1 and 10μM. The concentration-dependent protection was observed in H(2)O(2)- and glutamate-induced cellular injury. In in vivo studies, NP-647 treatment showed protection of hippocampal (CA1) neuronal damage in transient global ischemia in mice and subsequent improvement in memory retention was observed using passive avoidance retention test. Moreover, administration of NP-647 resulted in decrease in inflammatory cytokines TNF-α and IL-6 as well as lipid peroxidation. These results suggest potential of NP-647 in the treatment of cerebral ischemia and its neuroprotective effect may be attributed to reduction of excitotoxicity, oxidative stress and inflammation.
authors.affiliation: Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar, (Mohali), Punjab 160 062, India.
authors.forename: Satyendra Kumar
authors.initials: SK
authors.lastname: Rajput
authors.forename: Maqsood Ahmad
authors.initials: MA
authors.lastname: Siddiqui
authors.forename: Vivek
authors.initials: V
authors.lastname: Kumar
authors.forename: Chhuttan Lal
authors.initials: CL
authors.lastname: Meena
authors.forename: Aditya Bhushan
authors.initials: AB
authors.lastname: Pant
authors.forename: Rahul
authors.initials: R
authors.lastname: Jain
authors.forename: Shyam Sunder
authors.initials: SS
authors.lastname: Sharma
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D004195:Disease Models, Animal; D005947:Glucose / Q000172:deficiency; D018698:Glutamic Acid / Q000009:adverse effects; D006861:Hydrogen Peroxide / Q000009:adverse effects; D007249:Inflammation / Q000188:drug therapy; D015850:Interleukin-6 / Q000096:biosynthesis; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D013973:Thyrotropin-Releasing Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015850:Interleukin-6; D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha; C539979:pyroglutamyl-(2-propyl)histidyl-prolinamide; D018698:Glutamic Acid; D013973:Thyrotropin-Releasing Hormone; D006861:Hydrogen Peroxide; D005947:Glucose; D010100:Oxygen