Intraspinal injection of adenosine agonists protect against L-NAME induced neuronal loss in the rat.
Intraspinal injection of the nonspecific inhibitor of nitric oxide synthase N-nitro-L-arginine methyl ester (L-NAME) results in a dose-dependent loss of neurons in the rat spinal cord. This effect is thought to result from a reduction in basal levels of nitric oxide (NO), thereby producing an ischemic reaction secondary to vasoconstriction and reduced spinal cord blood flow (SCBF). An important component of this ischemic reaction is the release of excitatory amino acids and the initiation of an excitotoxic cascade. In the present study, microinjections of adenosine A1 and A2 receptor agonists were made in the spinal cord to evaluate the neuroprotective effects of these drugs against neuronal loss produced by L-NAME. Animals were divided into six groups based on the composition of injected solutions: (a) L-NAME; (b) L-NAME + N6-cyclopentyladenosine (CPA, A1 agonist); (c) L-NAME + 5'-(N-cyclopropyl)-carboxamidoadenosine (CPCA, A2 agonist); (d) L-NAME + CPA + CPCA; (e) N-methyl D-aspartate (NMDA); and (f) NMDA + CPA. Injections of L-NAME or NMDA produced a unilateral loss of spinal neurons, a local inflammatory response, and darkly stained pyknotic nuclei surrounding the area of neuronal loss. CPA and CPCA significantly reduced the area of L-NAME-induced neuronal loss, and a synergistic effect was observed when ineffective doses of these agonists were co-injected with L-NAME. The excitotoxic effects of NMDA were not affected by CPA. The results have shown that A1 and A2 receptor agonists provide significant neuroprotection against L-NAME induced neuronal loss, presumably by inhibiting ischemia induced release of excitatory amino acids (A1 agonist), or by restoring SCBF secondary to vasodilation (A2 agonist). It is suggested by these results that the intraspinal injection of L-NAME is an effective model to study the pathological consequences of vasoconstriction, reduced SCBF, and ischemia secondary to decreased NO production in the rat spinal cord. Finally, the results provide support for the continued investigation of specific adenosine agonists as therapeutic agents directed against the ischemic and excitotoxic components of spinal injury.
The Miami Project to Cure Paralysis, University of Miami, Florida, USA.
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Dora
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Koch
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Sanchez
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Ruenes
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Liu
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Yezierski
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004195:Disease Models, Animal; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000009:adverse effects; D007278:Injections, Spinal; D008297:Male; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000009:adverse effects; D019331:NG-Nitroarginine Methyl Ester / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D058906:Purinergic P1 Receptor Agonists; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D020318:Rats, Long-Evans; D013116:Spinal Cord / Q000187:drug effects* / Q000473:pathology
D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D058906:Purinergic P1 Receptor Agonists; D058910:Purinergic P2 Receptor Agonists; C048599:N(6)-cyclopentyladenosine; C024311:N-cyclopropyl adenosine-5'-carboxamide; D016202:N-Methylaspartate; D000241:Adenosine; D019331:NG-Nitroarginine Methyl Ester