title: Neuroprotective effects of lamotrigine in global ischemia in gerbils. A histological, in vivo microdialysis and behavioral study.
abstract: A sudden surge in the release of glutamate is currently believed to be an important initiating step in neuronal damage due to an ischemic insult. In this experiment, we tested the efficacy of neuroprotection with lamotrigine, a novel antiepileptic drug that blocks voltage gated sodium channels and inhibits the ischemia-induced release of glutamate in the gerbil forebrain model of cerebral ischemia. The medication was administered 30 min before and 30 min after the insult in two groups of animals. Histological assessment of neuronal damage was evaluated at 7 and 28 days after the ischemic insult. Animals evaluated at 28 days also underwent behavioral testing. Microdialysis was used in the same model to study the response of ischemia-induced glutamate in saline treated controls versus animals treated with lamotrigine 20 min before the insult. There was highly significant neuronal protection in animals who were treated with lamotrigine either before or after the insult. Protection was seen both at 7 and 28 days after the insult. Behavioral testing also showed significantly better recovery in both sets of animals in comparison to the saline-treated group. Microdialysis confirmed a significant attenuation of the ischemia-induced glutamate surge when compared to the saline-treated animals. Our morphological, behavioral and microdialysis experiments show that lamotrigine offers significant neuroprotection from the effects of transient forebrain ischemia in gerbils. Neuroprotection with post-ischemic therapy probably depends on preserving the capacity of the sodium/calcium exchanger to reduce intracellular calcium concentrations or persistent 'toxicity' of glutamate in the reperfusion period on the already 'primed' injured neurons. These concepts need further study.
authors.affiliation: Department of Medicine, University of Saskatchewan, Saskatoon, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Shuaib
authors.forename: R H
authors.initials: RH
authors.lastname: Mahmood
authors.forename: T
authors.initials: T
authors.lastname: Wishart
authors.forename: R
authors.initials: R
authors.lastname: Kanthan
authors.forename: M A
authors.initials: MA
authors.lastname: Murabit
authors.forename: S
authors.initials: S
authors.lastname: Ijaz
authors.forename: H
authors.initials: H
authors.lastname: Miyashita
authors.forename: W
authors.initials: W
authors.lastname: Howlett
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D002545:Brain Ischemia / Q000188:drug therapy*; D005849:Gerbillinae; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects; D000077213:Lamotrigine; D008297:Male; D017551:Microdialysis; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors; D014227:Triazines / Q000494:pharmacology*
chemical_list: D000927:Anticonvulsants; D014227:Triazines; D018698:Glutamic Acid; D000077213:Lamotrigine