The β2-adrenoceptor agonist clenbuterol elicits neuroprotective, anti-inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity.
Excitotoxicity is a mechanism of neuronal cell death implicated in a range of neurodegenerative conditions. Systemic administration of the excitotoxin kainic acid (KA) induces inflammation and apoptosis in the hippocampus, resulting in neuronal loss. Evidence indicates that stimulation of glial β(2)-adrenoceptors has anti-inflammatory and neurotrophic properties that could result in neuroprotection. Consequently, in this study we examined the effect of the β(2)-adrenoceptor agonist clenbuterol on KA-induced inflammation, neurotrophic factor expression and apoptosis in the hippocampus. Clenbuterol (0.5mg/kg) was administered to rats one hour prior to KA (10mg/kg). Epileptic behaviour induced by KA was assessed for three hours following administration using the Racine scale. Twenty-four hours later TUNEL staining in the CA3 hippocampal subfield and hippocampal caspase-3 activity was assessed to measure KA-induced apoptosis. In addition, expression of inflammatory cytokines (IL-1β and IFN-γ), inducible nitric oxide synthase (iNOS), kynurenine pathway enzymes indolamine 2,3-dioxygenase (IDO) and kynurenine monooxygenase (KMO), the microglial activation marker CD11b, and the neurotrophins BDNF and NGF were quantified in the hippocampus using real-time PCR. Whilst clenbuterol treatment did not significantly alter KA-induced epileptic behavior it ameliorated KA-induced apoptosis, and this neuroprotective effect was accompanied by reduced inflammatory cytokine expression, reduced expression of iNOS, IDO, KMO and CD11b, coupled with increased BDNF and NGF expression in KA-treated rats. In conclusion, the β(2)-adrenoceptor agonist clenbuterol has anti-inflammatory and neurotrophic actions and elicits a neuroprotective effect in the KA model of neurodegeneration.
Gleeson
Lorna C
LC
Neuropsychopharmacology Research Group, School of Pharmacy and Pharmaceutical Sciences, Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland.
Ryan
Katie J
KJ
Griffin
Eadaoin W
EW
Connor
Thomas J
TJ
Harkin
Andrew
A
D058667:Adrenergic beta-3 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002976:Clenbuterol / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D006624:Hippocampus / Q000473:pathology; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D008297:Male; D009414:Nerve Growth Factors / Q000378:metabolism*; D018696:Neuroprotective Agents; D020258:Neurotoxicity Syndromes / Q000473:pathology / Q000517:prevention & control*; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
D058667:Adrenergic beta-3 Receptor Agonists; D000893:Anti-Inflammatory Agents; D019208:Brain-Derived Neurotrophic Factor; D018690:Excitatory Amino Acid Agonists; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D009498:Neurotoxins; D053148:Caspase 3; D007608:Kainic Acid; D002976:Clenbuterol