Cerebral ischaemia

At the present time it is difficult to single out any one factor that could be held ultimately responsible for cell death after cerebral ischaemia. Recent studies, however, have provided us with sufficient evidence to conclude that free radical damage is at least one component in a chain of events that leads to cell death in ischaemia/reperfiision injury. As noted earlier in this review, much of the evidence for free radicals in the brain and the sources of free radicals come from studies in animals subjected to cerebral ischaemia. Perhaps the best evidence for a role for free radicals or reactive oxygen species in cerebral ischaemia is derived from studies that demonstrate protective effects of antioxidants. Antioxidants and inhibitors of lipid peroxidation have been shown to have profound protective effects in models of cerebral ischaemia. Details of some of these studies will be mentioned later. Several reviews have been written on the role of oxygen radicals in cerebral ischaemia (Braughler and HaU, 1989 Hall and Btaughler, 1989 Kontos, 1989 Floyd, 1990 Nelson ef /., 1992 Panetta and Clemens, 1993). 

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PI (adenosine) receptors were explored as therapeutic targets before P2 receptors. Adenosine was identified early and is in current use to treat supraventricular tachycardia. A2a receptor antagonists are being investigated for the treatment of Parkinson s disease and patents have been lodged for the application of PI receptor subtype agonists and antagonists for myocardial ischaemia and reperfusion injury, cerebral ischaemia, stroke, intermittent claudication and renal insufficiency. 

Ma J, Endres M, Moskowitz MA. Synergistic effects of caspase inhibitors and mk-801 in brain injury after transient focal cerebral ischaemia in mice. Br J Pharmacol 1998 124 756-762. 

The European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) confirmed the finding of ESPS 2, showing that the combination of aspirin and dipyridamole is more effective than aspirin alone in the prevention of new vascular events in patients with nondisabling cerebral ischaemia of presumed arterial origin. Adding the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death, stroke, or MI of 0.82 (95% Cl 0.74-0.91). 

ESPRIT Study Group, Halkes PH, van Gijn J, Kappelle LJ, Koudstaal PJ, Algra A. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT) randomised controlled trial. Lancet 2006 367(9523) 1665-1673. 

The proposal that NO or its reactant products mediate toxicity in the brain remains controversial in part because of the use of non-selective agents such as those listed above that block NO formation in neuronal, glial, and vascular compartments. Nevertheless, a major area of research has been into the potential role of NO in neuronal excitotoxicity. Functional deficits following cerebral ischaemia are consistently reduced by blockers of NOS and in mutant mice deficient in NOS activity, infarct volumes were significantly smaller one to three days after cerebral artery occlusion, and the neurological deficits were less than those in normal mice. Changes in blood flow or vascular anatomy did not account for these differences. By contrast, infarct size in the mutant became larger... 

Radical Production during Normal 4.1 Cerebral Ischaemia 77... 

NADH, which enters the Krebs cycle. However, during cerebral ischaemia, metabolism becomes anaerobic, which results in a precipitous decrease in tissue pH to below 6.2 (Smith etal., 1986 Vonhanweh etal., 1986). Tissue acidosis can now promote iron-catalysed free-radical reactions via the decompartmentalization of protein-bound iron (Rehncrona etal., 1989). Superoxide anion radical also has the ability to increase the low molecular weight iron pool by releasing iron from ferritin reductively (Thomas etal., 1985). Low molecular weight iron species have been detected in the brain in response to cardiac arrest. The increase in iron coincided with an increase in malondialdehyde (MDA) and conjugated dienes during the recirculation period (Krause et al., 1985 Nayini et al., 1985). 

The most extensive evidence that supports a role for free radicals in pathological conditions of the brain is provided by studies on experimental models of cerebral ischaemia/reperfusion. Although a burst of free-radical production occurs during the reperfusion phase after temporary cerebral ischaemia, the contribution of this radical burst to brain cell death can not be directly quantified. Perhaps the best way to quantify the contribution of free radicals to brain damage after ischaemia/ reperfusion is to assess damage after treatment with free-radical scavengers or antioxidants. Numerous studies have been reported where free-radical scavengers/ antioxidants have been used to try to ameliorate brain... 

It has been revealed that cannabinoids exhibit neuroprotectant activities in both in vitro and in vivo models [249]. The neuroprotective effects are mainly based on regulation of transmitter release, modulation of calcium homeostasis, anti-oxidant properties and modulation of immune responses. A number of neurological disorders, including brain trauma, cerebral ischaemia, Parkinson s disease and Alzheimer s disease represent possible therapeutic areas for cannabinoids with neuroprotective properties. Cannabinoids are also suggested to have potential against glaucoma due to their neuroprotective nature and lowering of intraocular pressure [250]. 

Kristian, T. and Siesjo, B. K. Changes in ionic fluxes during cerebral ischaemia. Int. Rev. Neurobiol. 40 27-45,1997. 

O Neill, M. J., Bond, A., Omstein, P. L., Ward, M. A., Hicks, C. A., Hoo, K., et al. (1998) Decahydroisoquinolines novel competitive AMPA/kainate antagonists with neuroprotec-tive effects in global cerebral ischaemia. Neuropharmacology 37,1211-1222. 

Gajewski A, Hensch SA. (1999). Ginkgo biloba and memory for a maze. Psychol Rep. 84(2) 481-84. Garg RK, Nag D, Agrawal A. (1995). A double blind placebo controlled trial of Ginkgo biloba extract in acute cerebral ischaemia. J Assoc Physicians India. 43(11) 760-63. 

Kochs E. 1997. Monitoring of cerebral ischaemia. Acta Anaes-thesiol Scand Suppl 111 92-95. 

Stenzel-Poore MP, Stevens SL, Xiong Z, Lessov NS, Harrington GA, et al. 2003. Effect of ischaemic preconditioning on genomic response to cerebral ischaemia similarity to neuroprotective strategies in hibernation and hypoxia-tolerant states. Lancet 362 1028. 

Wahlgren NG, Ahmed N. 2004. Neuroprotection in cerebral ischaemia facts and fancies - the need for new approaches. Cerebrovasc Dis 1 153. 

In addition to epilepsy, neuronal death due to the toxic effects of glutamate has also been implicated in cerebral ischaemia associated with multi-infarct dementia and possibly Alzheimer s disease. With the plethora of selective excitatory amino acid receptor antagonists currently undergoing development, some of which are already in clinical trials, one may expect definite advances in the drug treatment of neurodegenerative disorders in the near future. 

There is evidence that in cerebral ischaemia adenosine may have protective effects, since it inhibits the release of many excitatory neurotransmitters, such as glutamate, and it also stabilises the membrane potential. Unfortunately, adenosine has an extremely short half-life, but recently nucleoside (adenosine) transport inhibitors, e.g. draflazine, have been developed that prevent the endothelial uptake and breakdown of adenosine and prolong its beneficial effects. Nucleoside transport inhibitors also have myocardial protective properties and may have a role in organ preservation prior to transplantation. Adenosine also has an antinociceptive function and various adenosine analogues have antinociceptive activity, which correlates with their affinity for the A1 receptors (Lipkowski and co-workers 1996). 

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