Abstract
Kainic acid (KA) is well-known as an excitatory, neurotoxic substance. In mice, KA administered intracerebroventricularly (i.c.v.) lead to morphological damage of hippocampus expecially concentrated on the CA3 pyramidal neurons. In the present study, the possible role of gamma-aminobutyric acid B (GABA(B)) receptors in hippocampal cell death induced by KA (0.1 microg) administered i.c.v. was examined. 5-Aminovaleric acid (5-AV; GABA(B) receptors antagonist, 20 mug) reduced KA-induced CA3 pyramidal cell death. KA increased the phosphorylated extracellular signal-regulated kinase (p-ERK) and Ca(2+)/calmodulin-dependent protein kinase II (p-CaMK II) immunoreactivities (IRs) 30 min after KA treatment, and c-Fos, c-Jun IR 2 h, and glial fibrillary acidic protein (GFAP), complement receptor type 3 (OX-42) IR 1 day in hippocampal area in KA-injected mice. 5-AV attenuated KA-induced p-CaMK II, GFAP and OX-42 IR in the hippocampal CA3 region. These results suggest that p-CaMK II may play as an important regulator on hippocampal cell death induced by KA administered i.c.v. in mice. Activated astrocytes, which was presented by GFAP IR, and activated microglia, which was presented by the OX-42 IR, may be a good indicator for measuring the cell death in hippocampal regions by KA excitotoxicity. Furthermore, it showed that GABA(B) receptors appear to be involved in hippocampal CA3 pyramidal cell death induced by KA administered i.c.v. in mice.
Highlights
Kainic acid (KA), the analog of the excitatory amino acid L-glutamate, upon binding to non-NMDA glutamate receptors, causes depolarization of neurons followed by severe status epilepticus, neurodegeneration, plasticity, memory loss, neuronal cell death (Kaminska et al, 1997; Izquierdo et al, 2000; Zagulska-Szymczak et al, 2001)
5-Aminovaleric acid (5-AV) (20 μg, i.c.v.), γ-aminobutyric acid B (GABAB) receptors antagonist, showed a protective effect significantly against the hippocampal cell death induced by i.c.v. administered KA
Immunocytochemical studies have revealed that GABAB receptors are distributed throughout the striatum, hippocampus, dentate gyrus (DG), hypothalamus, tectum, cerebellum, brainstem and spinal cord of rat (Fritschy et al, 1999; Margeta-Mitrovic et al, 1999; Calver et al, 2000)
Summary
Kainic acid (KA), the analog of the excitatory amino acid L-glutamate, upon binding to non-NMDA glutamate receptors, causes depolarization of neurons followed by severe status epilepticus, neurodegeneration, plasticity, memory loss, neuronal cell death (Kaminska et al, 1997; Izquierdo et al, 2000; Zagulska-Szymczak et al, 2001). The systemic or intracerebroventriculary (i.c.v.) KA injection produces a pyramidal cell death in CA1 or CA3 region of hippocampus. Delayed neuronal death is seen in the rat hippocampus CA1 and CA3 by KA administered intraperitoneally in the cresyl violet staining and TUNEL assay (Baik et al, 1999). Neuronal loss is found in the CA1 and CA3 subfields of the rat hippocampus following by i.c.v. KA administration (Roe et al, 1998; Matsuoka et al, 1999). KA, administered i.c.v., induced the lesion of CA3 pyramidal neurons in mice (Ferraguti et al, 2001; Lee et al, 2002; Lee et al, 2003)
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