The Neuroprotective Effects of a Kappa-Opioid Agonist and Its Mechanistic Basis

Mackay, Kenneth B (1994) The Neuroprotective Effects of a Kappa-Opioid Agonist and Its Mechanistic Basis. PhD thesis, University of Glasgow.

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The main aims of this thesis were to investigate the effects of the potent and selective k-opioid agonist CI-977 in animal models of focal cerebral ischaemia, and gain insight into a possible mechanism of action underlying the anti-ischaemic efficacy of k-agonists. Quantitative neuropathology was used to determine the effect of CI-977 on the volume of ischaemic brain damage after permanent middle cerebral (MCA) occlusion in the rat (outcome assessed at 24h and 4h) and cat (outcome assessed at 6h). Microdialysis techniques were employed in vivo to examine the effects of CI-977 on glutamate release after MCA occlusion in the cat and also on neuronal necrosis induced by exogenous glutamate perfused into the rat cerebral cortex by reverse dialysis. The cerebral circulatory effects of CI-977 were examined in the rat using [14C]-iodoantipyrine autoradiography in normal brain and after permanent MCA occlusion, and in the cat after the induction of focal ischaemia using the hydrogen clearance technique. [14C]-2-Deoxyglucose in vivo autoradiography was employed to assess the functional consequences as reflected in alterations in local rates of cerebral glucose utilisation in discrete brain regions in conscious rats following the systemic administration of CI-977. The administration of CI-977 (0.03, 0.3 or 3mg/kg, s.c.) initiated 30 min prior to occlusion of the MCA in the rat (and at multiple times thereafter) produced dose-dependent reductions in the volumes of infarction and of brain swelling when assessed at 24h. The most marked reductions were noted with CI-977 (0.3mg/kg) in both infarction (reduced by 38% from controls) and swelling (reduced by 31%). There was an excellent correlation between the volume of brain swelling and ischaemic damage which was similar for vehicle-treated and CI-977-treated animals (overall correlation coefficient r=0.896). Treatment with CI-977 (0.3mg/kg, s.c.) 30 min before and 30 min after permanent MCA occlusion in halothane- anaesthetised rats significantly reduced the volume of infarction in the cerebral hemisphere (reduced by 27%) and cerebral cortex (reduced by 32%) despite a marked and sustained hypotension, with only minimal effect on ischaemic damage in the caudate nucleus. Pretreatment with CI-977 (0.3mg/kg i.v. bolus followed by continuous i.v. infusion of 0.15mg/kg/h until death) initiated 15 min prior to MCA occlusion significantly reduced the volume of ischaemic brain damage in the cerebral hemisphere (reduced by 33%) and cerebral cortex (reduced by 42%) in halothane-anaesthetised cats without altering significantly any of the key physiological parameters monitored throughout the post-occlusion survival period. In a parallel study, the effects of CI-977 (0.3mg/kg, s.c.) on cerebral blood flow were examined 30 min after the induction of ischaemia in halothane-anaesthetised rats. In the hemisphere contralateral to the occluded MCA, pretreatment with CI-977 failed to demonstrate any significant effect on the level of local cerebral blood flow in any of the 25 regions examined. In the hemisphere ipsilateral to MCA occlusion, CI-977 failed to produce statistically significant alterations in either the level of local cerebral blood flow in 23 of the 25 regions or on the volume of hypoperfused tissue determined by frequency distribution analysis. Areas of hyperaemia were observed in CI-977-treated rats with MCA occlusion in both the medial caudate nucleus and lateral thalamus (local cerebral blood flow increased by 65% and 86% respectively compared to vehicle). In an in vivo model of glutamate neurotoxicity in anaesthetised rats, pre-and post-treatment with CI-977 (0.3mg/kg, i.v.) had no significant effect on the volume of neuronal necrosis assessed 4h after the onset of glutamate (0.5M) perfusion into the parietal cortex; the NMDA antagonist MK-801 (0.5mg/kg) and the AMPA antagonists (2 x 30mg/kg) significantly reduced the lesion volume by 30% and 23% respectively. Permanent occlusion of the MCA in halothane-anaesthetised cats produced a marked increase in extracellular glutamate levels, determined by microdialysis, when cerebral blood flow fell to a threshold value of approximately 20ml 100g-1 min-1 in vehicle-treated control animals. The administration of CI-977 (0.3mg/kg i.v. plus an i.v. infusion of 0.15mg/kg/h) 30 min prior to the induction of ischaemia produced no evidence of such a threshold for glutamate release in the ischaemic hemisphere, and markedly attenuated the increase in extracellular glutamate concentration at cerebral blood flow values of less than 20ml 100g-1 min-1. The results of the studies within this thesis suggest that a major component of the mechanism of action which underlies the anti-ischaemic efficacy of CI-977 in animal models of ischaemia is a presynaptic inhibition of glutamate release. Thus k-opioid agonists such as CI-977 may be of benefit therapeutically for modulating excitotocxic brain damage in cerebral ischaemia in man, and their use is unlikely to be complicated by concerns over CNS safety as with NMDA receptor antagonists.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: James McCulloch
Keywords: Neurosciences
Date of Award: 1994
Depositing User: Enlighten Team
Unique ID: glathesis:1994-74963
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 27 Sep 2019 14:58
Last Modified: 27 Sep 2019 14:58

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