INABIS Y2K, Poster #93, Matsuoka et al. Introduction

Introduction

Adenosine is a purine nucleotide with diverse biological functions. Purinergic receptors can be divided into two subgroups based on their agonist preference for adenosine (P1) or ATP (P2) (Fredholm et al., 1994). Adenosine receptors, also referred to as P1 purinoceptors, are members of the G protein-coupled receptor family that mediate the physiological effects of adenosine. The A1, A2a, A2b, and A3 adenosine receptor subtypes have been cloned (Olah and Stiles, 1995). These adenosine receptor subtypes show distinct distributions, and the A1 and A2a subtypes are expressed predominantly in the CNS (Fredholm et al., 1994). In the CNS, adenosine modulates synaptic transmission by blocking neurotransmitter release (Hollins and Stone, 1980; Ribeiro and Sebastiao, 1984), modulates long-term potentiation in the hippocampus (de Mendonca and Ribeiro, 1994), and affects cerebral blood flow (Phillis and Wu, 1981). Adenosine A1 receptors are known to mediate the suppression of neuronal activity in the hippocampus (Dunwiddie and Fredholm, 1989).
Cerebral ischemia results in the release of large amounts of excitatory amino acid transmitter, such as glutamate, into the extracellular space. This release is mirrored by a drastic increase in the extracellular concentration of adenosine (Globus et al., 1988; Hagberg et al., 1987). In addition, adenosine analog blocks experimentally-induced seizures in animals (Barraco et al., 1984), and electrical stimulation along with adenosine receptor antagonist induces status epilepticus (Young and Dragunow, 1995). Therefore, adenosine may act as an endogenous anticonvulsant (Dragunow et al., 1985; During and Spencer, 1992). Furthermore, binding to the A1 adenosine receptor is decreased in human temporal lobe epilepsy (Glass et al., 1996). Although these results strongly suggest that adenosine may participate in seizure and may exert neuroprotection, the role of endogenous adenosine in cell vulnerability has not yet been examined.
Kainic acid (KA) is a potent agonist at excitatory amino acid receptor subtypes in the CNS. Intracerebroventricular (i.c.v.) injection of KA induces selective neuronal loss in the CA3 subfield and activates glial cells in the rat hippocampus (Nalder et al., 1980). In addition, selective neuronal vulnerability has been reported; i.e., hypoxia, a main cause of ischemia, induced neurodegeneration in the CA3, but not in the CA1 (Taniguchi et al., 1994; Matsuoka et al., 1995, 1997a and 1997b), although the CA1 is vulnerable to ischemic stimuli (Kirino, 1982). Evidence for the neurodegenerative mechanisms of glutamate has accumulated (Dykens et al., 1987; Coyle and Puttfarcken, 1993). However, the molecular and cellular events responsible for the selective vulnerability of this population of neuronal cells to KA-induced seizure activity are not yet understood. Therefore, we tried to clarify the mechanism of selective neuronal vulnerability in the hippocampus by focusing on the A1 adenosine receptor in an animal model of KA-induced neurodegeneration, using microtubule associated protein-2 (MAP-2)-; phosphorylated c-Jun-; and CD11b-, glial fibrillary acidic protein (GFAP)-, and major histocompatibility complex (MHC) class II-immunoreactivities as markers for neuronal cell loss, neuronal apoptosis, and glial activation, respectively.