title: JAK2 inhibition is neuroprotective and reduces astrogliosis after quinolinic acid striatal lesion in adult mice.
abstract: Quinolinic acid (QA) striatal lesion in rodents induces neuronal death, astrogliosis and migration of neuroblasts from subventricular zone to damaged striatum. These phenomena occur in some human neurodegenerative illnesses, but the underlying mechanisms are unknown. We investigated the effect of AG490, a Janus-kinase 2 (JAK2) inhibitor, on astrogliosis, neuronal loss and neurogenesis in the striatum of adult mice after unilateral infusion of QA (30 nmol). Animals were given subcutaneous injections of AG490 (10 mg/kg) or vehicle immediately after lesion and then once daily for six days. Brain sections were used for neuronal stereological quantification, immunohistochemical and Western Blotting analyses for GFAP and doublecortin, markers of astrocytes and neuroblasts, respectively. The total area of doublecortin-positive cells (ADPC) and the number of neurons (NN) in the lesioned (L) and contralateral (CL) sides were evaluated. Neurogenesis index (NI=ADPC(L)/ADPC(CL)) and neuronal ratio (NR=NN(L)/NN(CL)) were calculated. After QA administration, blotting for GFAP showed an ipsilateral decrease of 19% in AG490- vs vehicle-treated animals. NR was 25% higher in mice given AG490 vs controls given vehicle. NI showed a decrease of 21% in AG490- vs vehicle-treated mice. Our results indicate that JAK2 inhibition reduces QA lesion and suggest that astrogliosis may impair neuronal survival in this model.
authors: Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, UNICAMP, Barão Geraldo, Campinas, SP, Brazil.
authors: Raffaela Silvestre
authors: RS
authors: Ignarro
authors: André Schwambach
authors: AS
authors: Vieira
authors: Cesar Renato
authors: CR
authors: Sartori
authors: Francesco
authors: F
authors: Langone
authors: Fábio
authors: F
authors: Rogério
authors: Carlos Amilcar
authors: CA
authors: Parada
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects*; D015153:Blotting, Western; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005904:Glial Fibrillary Acidic Protein / Q000096:biosynthesis / Q000235:genetics; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007150:Immunohistochemistry; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D017072:Neostriatum / Q000473:pathology*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents; D010766:Phosphorylation; D017378:Quinolinic Acid; D050791:STAT Transcription Factors / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020032:Tyrphostins / Q000494:pharmacology*
chemical_list: D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D050791:STAT Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D017378:Quinolinic Acid