title: Neuroprotective effects of lamotrigine and remacemide on excitotoxicity induced by glutamate agonists in isolated chick retina.
abstract: The possible neuroprotective effects of two recently developed antiepileptic compounds, lamotrigine (LTG) and remacemide (REMA), against glutamate agonist-induced excitotoxicity have been investigated in the isolated chick embryo retina model. Retina segments from 15- or 16-day-old embryos were incubated in 1 ml of balanced salt solution, at 25 degrees C for 30 min, in the presence or absence of N-methyl-d-aspartate (NMDA), kainic acid (KA), or alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) (10 to 200 microM). LTG, REMA, and the active desglycinyl metabolite of REMA (d-REMA) (10-200 microM) were added separately 5 min before glutamate agonists. Retina damage was assessed after 24 h (i) by measuring LDH activity present in the medium, expressed as percentage of total retina LDH activity, and (ii) by histological analysis of retina specimens through scoring for the presence or absence of edema, necrosis, nuclear pyknosis, and cell layer damage. LTG, REMA, and d-REMA reduced LDH release produced by NMDA 58-70% in a dose-dependent manner, with d-REMA being the most potent (EC(50): d-REMA, 25.75 +/- 3.27 microM; REMA, 64.75 +/- 7.75 microM; LTG, 60.50 +/- 6.80 microM; P < 0.001). The drugs had less effect on the LDH release produced by AMPA and KA. Histological analysis confirmed these biochemical results, with all three compounds reducing edema and the number of necrotic and pyknotic nuclei in the ganglion layer. d-REMA provided almost complete protection of the ganglion cell layer against damage produced by NMDA. Combinations of d-REMA and LTG showed additive rather than potentiative effects against NMDA-induced cell injury. The present data provide pharmacological evidence that LTG, REMA, and d-REMA decrease glutamate agonist-induced excitotoxicity in isolated chick retina, findings that might have therapeutic implications for various neurological disorders.
authors: Istituto di Scienze Biochimiche e Biochimica Clinica, University of Messina, 98100 Messina, Italy.
authors: F
authors: F
authors: Pisani
authors: S
authors: S
authors: Pedale
authors: V
authors: V
authors: Macaione
authors: V
authors: V
authors: Torre
authors: G
authors: G
authors: Oteri
authors: G
authors: G
authors: Avanzini
authors: R
authors: R
authors: Ientile
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000077213:Lamotrigine; D016202:N-Methylaspartate / Q000633:toxicity; D009336:Necrosis; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010627:Phenethylamines / Q000494:pharmacology; D012160:Retina / Q000166:cytology / Q000187:drug effects* / Q000196:embryology; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects; D014227:Triazines / Q000494:pharmacology*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
chemical_list: D000081:Acetamides; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D010627:Phenethylamines; D014227:Triazines; C089135:FPL 12495; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D007770:L-Lactate Dehydrogenase; C067553:remacemide; D007608:Kainic Acid; D000077213:Lamotrigine