Graduate Thesis Or Dissertation
 

Adenosine analogs suppress seizures induced by bicuculline methiodide in the rat prepiriform cortex

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  • Although considerable experimental evidence suggests that endogenous adenosine may function as a modulator of neuronal activity in the etiology or control of seizures, the neuroanatomical and neurochemical basis for the anticonvulsant actions of adenosine have not been well established. A discrete brain region of possible fundamental importance to epileptogenisis within the rat prepiriform cortex (PC) has been described (Piredda and Gale, 1985). The objectives of this study were to determine whether adenosine analogs exert anticonvulsant effects by an action at the seizure focus - a site within the PC, - elicited by a chemoconvulsant, bicuculline; and to pharmacologically characterize the adenosine receptor mediating the seizure suppressant effects in the rat prepiriform cortex. Unilateral focal microinjection of 118 pmol bicuculline methiodide (BMI) into the PC elicited bilateral motor seizures and these seizures were potently inhibited by prior injection of the adenosine receptor agonist, 2-chloroadenosine (2-C1A). In addition, this anticonvulsant action of 2-C1A at a dose of 41.4 pmol was completely prevented when co-administered with the specific adenosine receptor antagonist 8-(p-sulfophenyl) theophylline (8-pSPT). These results not only indicate that the PC is one potential site of adenosine modulation of seizure susceptibility, but also demonstrate that an activation of adenosine receptor is operative in the observed suppression of the behavioral seizures. Furthermore various adenosine analogs , N-ethylcarboxamidoadenosine (NECA), (-)N⁶-(Rphenylisopropyl) adenosine (R-PIA), (+)N⁶-(S-phenylisopropyl) adenosine (S-PIA), N⁶-cyclopentyladenosine (CPA) and N⁶-cyclohexyladenosine (CHA) were applied to the PC and produced a dose-dependent reduction in the severity of seizures evoked by BMI. The most potent analog tested was NECA with an ED₅₀ value as low as 4.0 ± 3.0 picomoles. Other adenosine analogs were also potent antiepileptic agents and had ED₅₀ values which ranged from 7.76 to 207.8 picomoles. The rank order potency was NECA ≥ CHA > CPA > R-PIA > 2-C1A » S-PIA. R-PIA was found to be 10.2 times more potent than its S-diastereoisomer as an antiepileptic in the PC. Finally, the selective A₂ adenosine receptor agonist, 2-phenylaminoadenosine (CV-1808), was devoid of seizure suppressant activity when focally injected in the PC in a dose as high as 334.8 picomole. This rank order potency, degree of stereoselectivity for R-PIA vs S-PIA and lack of anticonvulsant effect of CV-1808 suggest that activation of A₁ adenosine receptors is the basis for protection afforded by focal injections of these analogs against seizures induced by bicuculline from a site within the rat prepiriform cortex.
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