It has been postulated that endogenous kynurenic acid (KYNA) modulates ␣7* nicotinic acetylcholine receptor (nAChR) and NMDA receptor activities in the brain.a To test this hypothesis, ␣7* nAChR and NMDA receptor functions were studied in mice with a targeted null mutation in the gene encoding kynurenine aminotransferase II (mKat-2 ؊/؊ mice), an enzyme responsible for brain KYNA synthesis. At 21 postnatal days, mKat-2 ؊/؊ mice had lower hippocampal KYNA levels and higher spontaneous locomotor activity than wild-type (WT) mice. At this age, ␣7* nAChR activity induced by exogenous application of agonists to CA1 stratum radiatum interneurons was ϳ65% higher in mKat-2 ؊/؊ than WT mice. Binding studies indicated that the enhanced receptor activity may not have resulted from an increase in ␣7* nAChR number. In 21-d-old mKat-2 ؊/؊ mice, endogenous ␣7* nAChR activity in the hippocampus was also increased, leading to an enhancement of GABAergic activity impinging onto CA1 pyramidal neurons that could be reduced significantly by acute exposure to KYNA (100 nM). The activities of GABA A and NMDA receptors in the interneurons and of ␣3␤4* nAChRs regulating glutamate release onto these neurons were comparable between mKat-2 ؊/؊ and WT mice. By 60 d of age, KYNA levels and GABAergic transmission in the hippocampus and locomotor activity were similar between mKat-2 ؊/؊ and WT mice. Our findings that ␣7* nAChRs are major targets for KYNA in the brain may provide insights into the pathophysiology of schizophrenia and Alzheimer's disease, disorders in which brain KYNA levels are increased and ␣7* nAChR functions are impaired.

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SUMMARYPurpose: The aim of this work is to study, by means of computational simulations, the induction and sustaining of nonsynaptic epileptiform activity. Methods: The computational model consists of a network of cellular bodies of neurons and glial cells connected to a three-dimensional (3D) network of juxtaposed extracellular compartments. The extracellular electrodiffusion calculation was used to simulate the extracellular potential. Each cellular body was represented in terms of the transmembrane ionic transports (Na + /K + pumps, ionic channels, and cotransport mechanisms), the intercellular electrodiffusion through gap-junctions, and the neuronal interaction by electric field and the variation of cellular volume. Results: The computational model allows simulating the nonsynaptic epileptiform activity and the extracellular potential captured the main feature of the experimental measurements. The simulations of the concomitant ionic fluxes and concentrations can be used to propose the basic mechanisms involved in the induction and sustaining of the activities. Discussion: The simulations suggest: The bursting induction is mediated by the Cl ) Nernst potential overcoming the transmembrane potential in response to the extracellular [K + ] increase. The burst onset is characterized by a critical point defined by the instant when the Na + influx through its permeable ionic channels overcomes the Na + / K + pump electrogenic current. The burst finalization is defined by another critical point, when the electrogenic current of the Na + /K + pump overcomes its influx through the channels.

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We investigated the protective effect of suramin, an enzyme inhibitor and an uncoupler of G protein from receptors, on the myotoxic activity in mice of different crotalid snake venoms (A.c. laticinctus, C.v. viridis, C.d. terrificus, B. jararacussu, B. moojeni, B. alternatus, B. jararaca, L. muta). Myotoxicity was evaluated in vivo by injecting im the venoms (0.5 or 1.0 mg/kg) dissolved in physiological saline solution (0.1 ml) and measuring plasma creatine kinase (CK) activity. Two experimental approaches were used in mice (N = 5 for each group). In protocol A, 1 mg of each venom was incubated with 1.0 mg suramin (15 min, 37ºC, in vitro), and then injected im into the mice at a dose of 1.0 mg/kg (in vivo). In protocol B, venoms, 1.0 mg/kg, were injected im 15 min prior to suramin (1.0 mg/kg, iv). Before and 2 h after the im injection blood was collected by orbital puncture. Plasma was separated and stored at 4ºC for determination of CK activity using a diagnostic kit from Sigma. Preincubation of some venoms (C.v. viridis, A.c. laticinctus, C.d. terrificus and B. jararacussu) with suramin reduced (37-76%) the increase in plasma CK, except for B. alternatus, B. jararaca or L. muta venoms. Injection of suramin after the venom partially protected (34-51%) against the myotoxicity of B. jararacussu, A.c. laticinctus and C.d. terrificus venom, and did not protect against C.v. viridis, L. muta, B. moojeni, B. alternatus or B. jararaca venoms. These results show that suramin has an antimyotoxic effect against some, but not all the North and South American crotalid snake venoms studied here.

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