Pharmacological reduction of electrophysiological diaschisis after photothrombotic ischemia in rat neocortex.
Focal cerebral lesions in the rat brain induced by photothrombosis cause hyperexcitability of the surrounding brain. This can be demonstrated in brain slices taken from animals several days after lesioning, by analysis of field potential responses to paired-pulse stimulation. We now investigated whether and how these remote effects of a cortical lesion can be modified pharmacologically. Application of the NMDA receptor antagonist, MK-801 ((+)-5-methyl-10, 11-dihydro-5H-dibnzo[a,d]cyclohepten-5,10-imine), was shown to block induction of immediate early genes and activation of astrocytes as evidenced by glial fibrillary acidic protein (GFAP) staining in the photothrombosis model. However, MK-801 did not affect the hyperexcitability that had been demonstrated by field potential recordings in brain slices. In another series of experiments, lubeluzole ((+)-(S)-4-(2-benzothiazolylmethylamino)-alpha-[(3,4-difluoroph enoxy) methyl]-1-piperidineethanol), which inhibits the glutamate-activated nitric oxide pathway as evidenced by down-regulation of intracellular cyclic GMP, was given immediately after induction of the insult. This reduced hyperexcitability as investigated 7 days later. In the light of these data one can suggest that a nitric oxide-cyclic GMP-related mechanism may be responsible for functional alterations in the surround of photothrombotic brain lesions.
Buchkremer-Ratzmann
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Neurologische Klinik, Heinrich-Heine-Universität, Düsseldorf, Germany.
Witte
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D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000503:physiopathology*; D017484:Dermatitis, Phototoxic; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004594:Electrophysiology; D005071:Evoked Potentials / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D002542:Intracranial Embolism and Thrombosis / Q000150:complications* / Q000209:etiology / Q000503:physiopathology; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D013844:Thiazoles / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D013844:Thiazoles; D016291:Dizocilpine Maleate; C097722:lubeluzole