The 5HT1A receptor agonist, 8-OH-DPAT, protects neurons and reduces astroglial reaction after ischemic damage caused by cortical devascularization.
Serotonin 1A (5HT1A) receptor agonists have shown neuroprotective properties in different models of central nervous system injury. Activation of neuronal 5HT1A receptors appears to be involved in the neuroprotective effects. It remains to be elucidated if astroglial cells are responsive to the 5HT1A neuroprotective effects. The participation of astroglial S100B trophic factor has been proposed since 5HT1A activation leads to S100B release and nanomolar concentration level of this molecule showed pro-survival activity in neuronal cultures. Using the cortical devascularization model (CD; unilateral pial disruption), a procedure that results in localized ischemia without producing direct physical damage to brain tissue, we tested the effects of a full 5HT1A agonist, 8-OH-DPAT, or the antagonist WAY-100635 on cortical neuronal survival, astroglial cell response and S100B expression. Wistar rats were subjected to CD lesion which consisted of a craniotomy followed by physical damage to the underlying pial blood vessels. Two and twenty-four hours after the CD lesion, animals received intraperitoneally 8-OH-DPAT (1 mg/kg), WAY-100635 (1 mg/kg) or vehicle (sterile saline). At 3, 7 or 14 days post-lesion, animals were sacrificed and their brains processed for immunohistochemistry to detect GFAP, vimentin, MAP-2, S100B and nuclear Hoechst staining. S100B level in the brain cortex and serum was quantified by an ELISA assay. Serum S100B was considered an index of S100B release. 8-OH-DPAT treatment reduced neuronal death, dendrite loss, astroglial hypertrophy and hyperplasia. In contrast, WAY-100635 treatment increased these parameters of damage. S100B intracellular immunoreactivity in astrocytes and total S100B level showed long-lasting changes after the CD lesion and subsequent treatments depending on the 5HT1A activity. The level of serum S100B was increased in 8-OH-DPAT-treated animals. Increased damage observed in WAY-100635-treated animals supports the hypothesis that the protective 8-OH-DPAT action may be mediated by specific 5HT1A receptors. The reduction in astroglial hypertrophy and hyperplasia as well as long-term changes in S100B immunoreactivity and increased S100B release that we observed allows us to hypothesize that astroglial cells may play an important role in 5HT1A-mediated neuroprotection.
Ramos
Alberto Javier
AJ
Instituto de Biología Celular y Neurociencia Prof. E. De Robertis Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155 3er piso, 1121 Buenos Aires, Argentina. alberto.ramos@mcgill.ca
Rubio
María Dolores
MD
Defagot
Cristina
C
Hischberg
Lotta
L
Villar
Marcelo J
MJ
Brusco
Alicia
A
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D002544:Cerebral Infarction / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D008297:Male; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology
D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D010879:Piperazines; D011725:Pyridines; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579158:S100b protein, rat; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin