Beta 2 Adrenergic Agonist

S tud iesofm icetrea tedwi th a singleor repea ted dosesof mg kgof NP showed depressed mo toractivity a nd bi la teralsymmetriclesionsof thecaud ate putam en duced progressive imp airm entofmotorb eh av iorwith som ma ls lying on theirsideswi th theh indlimbsrigidly ex. Ultrast ructuralstud ies inbothmice and rats showeddend ro som aticswell ing, consistentwith an excito tox ic in jury. Thep atternof neuronalin ju ry cou ld notbeexp la ined by thedistr Benzyl alcohol ibution of inh ibit ionof succ in ate dehyd rogena se activity, since bio chem icalandhistochem icals tud ies showed it to be unifo rm throughoutthecerebralcortex and basal ganglia. Thelesions were hypo thesized to be duetohis to tox ic hypox ia, since NP inc reased arterialb lood cysteine pressure and ar ter ialb lood oxygen comp aredwith controls. Studies in cortical explants showed thatNP produces cel lular ATP depletion and neu ronaldamage by a secondary excitotoxic mechanism. Pathologic changes were significantly attenua ted bypretrea tmentwith excitatory am ino acid antagonists.In cultured cerebellar granule neu rons NP resulted in concentration and time. Both MK and the competitive NMDA an tagon istam inophosphonovaleric acid delayed butd id notprevent the NP toxicity.Beal and coworkers studied NP neurotoxicity in bo th rats and no nhum anprimates.In initial studies, the effects of intrastriatal injectionsof NP were examined. These in jections produced dosedependentlesions with neuronal loss and gliosis duced ATP depletions at hr, which persisted for up to hr after the injections. Using in vivo chemical shift magnetic resonance imaging we showed th at there were focal accumu lationsof lactate in the basal gan glia.Thelesions were strikingly agedependent, which was subsequently confirmed dence correlated directly with the increases in lactate fol lowing adm in istrationof a un iform doseof NP to an ima ls of various ages.Thelesions occurred by an excitotoxic mechan ism since pr ior decortication, which removes the striatal glutamatergic input, significantly attenua ted the le acute and chron ic adm in istrationof NP in rats.Subacu te adm in istration was performed by ip adm in istrationof NP over days.Th is resulted in the deve lopmentofmo tor slowing and dystonic pos tur ing in the rats.With very large lesions the re was accompany ing neuronalloss and gliosis in the CA fieldof thehippocampus and gliosis in the cerebral cortex.Smaller lesions were confined to the basal ganglia.No lesions were observed in the spinal cord, suggesting th at the movementd isorder was due to the striatal lesions.Systemic NP lesions were also attenua ted bypr iorde ins.Microdialysis studies showed thatthere was no signifi cantincrease in extracellularglu tama te concen trations. These results are consistent with NP causing excitotoxi elsof glutamate. We reasoned th ata chron ic low grade energydis turbance was mu ch mo re likely tomim ic thesi tuation which may occurin neurodegenerative dis digm resulted in subtle lesions confined to the dorsolateral str ia tum, in which there was neu ronalloss and gliosis. Furthe rmo re, this modeof adm in istration was associated with the sparingof NADPH diaphorase neurons, similar to findings in HD.

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