Ro5-4864, a peripheral benzodiazepine receptor ligand, reduces reactive gliosis and protects hippocampal hilar neurons from kainic acid excitotoxicity.
The peripheral-type benzodiazepine receptor (PBR) is a critical component of the mitochondrial permeability transition pore, which is involved in the regulation of cell survival. Different forms of brain injury result in induction of the expression of the PBR in the areas of neurodegeneration, mainly in reactive glial cells. The consequences of induction of PBR expression after brain injury are unknown. To test whether PBR may be involved in the regulation of neuronal survival after injury, we have assessed the effect of two PBR ligands, Ro5-4864 and PK11195, on neuronal loss induced by kainic acid in the hippocampus. Systemic administration of kainic acid to male rats resulted in the induction of a reactive phenotype in astrocytes and microglia and in a significant loss of hilar neurons in the dentate gyrus. Administration of Ro5-4864, before the injection of kainic acid, decreased reactive gliosis in the hilus and prevented hilar neuronal loss. In contrast, PK11195 was unable to reduce reactive gliosis and did not protect hilar neurons from kainic acid. These findings suggest that the PBR is involved in control of neuronal survival and gliosis after brain injury and identify this molecule as a potential target for neuroprotective interventions.
Veiga
Sergio
S
Instituto Cajal, C.S.I.C., Madrid, Spain.
Azcoitia
Iñigo
I
Garcia-Segura
Luis M
LM
D000818:Animals; D001570:Benzodiazepinones / Q000627:therapeutic use*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D005911:Gliosis / Q000139:chemically induced / Q000517:prevention & control*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007150:Immunohistochemistry; D007546:Isoquinolines / Q000494:pharmacology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D014746:Vimentin / Q000187:drug effects / Q000378:metabolism
D001570:Benzodiazepinones; D018690:Excitatory Amino Acid Agonists; D007546:Isoquinolines; D018696:Neuroprotective Agents; D018079:Receptors, GABA; D014746:Vimentin; C028513:4'-chlorodiazepam; D007608:Kainic Acid; C037850:PK 11195