Molecular Psychiatry (1997) 2, 120–121  1997 Stockton Press All rights reserved 1359–4184/97 $12.00 CYTOKINES IN THE BRAIN brain damage in the rat.4 The involvement of IL-1 in diverse forms of neurodegeneration is further sup- ported by observations that IL-1ra also reduces clini- Cytokines and acute cal symptoms of EAE (an experimental model of mul- tiple sclerosis), and neuronal loss caused by neonatal neurodegeneration hypoxia/ischaemia in rats and heat stroke in rabbits. NJ Rothwell The mechanisms of action of IL-1 or IL-1ra remain obscure. Both molecules appear to exert most potent School of Biological Sciences, University of Manchester, actions in the striatum in vivo, but there is no definitive 1.124 Stopford Building, Oxford Road, Manchester M13 explanation for this site-specificity. IL-1/IL-1ra appear 9PT, UK to act at a late stage in neurodegeneration beyond gluta- mate receptor activation, since IL-1ra also inhibits exci- totoxic brain damage caused by pharmacological acti- vation of NMDA or AMPA/KA receptors. Indirect actions of IL-1 on neurodegeneration through effects on Rapid overexpression of cytokines in the brain is now glia or brain endothelium have also been reported. It is becoming a recognised feature of diverse forms of thus possible that IL-1 has several actions which could experimental and clinical neurodegenerative con- explain its apparent involvement in such diverse forms ditions. This, together with the accepted involvement of neurodegeneration. of proinflammatory cytokines in systemic injury, infec- In spite of the growing weight of evidence supporting tion and inflammation, and the emerging influence of a major role for IL-1 in acute neurodegeneration, it is immune and inflammatory responses in CNS disease, likely that this molecule acts in synergy with other pro- infers a primary or causal role for cytokines in acute inflammatory cytokines, and the overall response to brain damage is probably also influenced by anti- neurodegeneration. inflammatory cytokines, including endogenous IL-1ra Some evidence does indeed support the direct which is induced by brain insults, slightly after IL-1, involvement of a number of proinflammatory cytokines and in different cells (neurons). (eg chemokines and tumor necrosis factor—TNF␣)in The clinical potential of modifying IL-1 synthesis acute neurodegeneration, but the most extensive sup- or action in neurodegeneration is attractive. Indeed, port and clinical potential rests with interleukin (IL- this cytokine has been implicated in many chronic as 1).1,2 Expression of IL-1 messenger RNA and protein well as acute neurological conditions, including mul- (predominantly the ␤ form) is apparent between 30 min tiple sclerosis, Parkinson’s disease and Alzheimer’s and 1 h after experimental brain injury, cerebral disease.5 At present the most effective, safe and well ischaemia or excitotoxic damage in rodents. The pri- tested (in clinical trials for systemic disease) means mary cell source of IL-1 is microglia and meningial of inhibiting IL-1 is through injection of IL-1ra. macrophages, though delayed expression also occurs Although IL-1ra is quite a large protein, it clearly can, in astrocytes and invading immune cells. and does, influence neurodegeneration when admin- Functional studies indicate that administration of istered systemically. The therapeutic benefit of IL-1ra recombinant IL-1 dramatically exacerbates acute in acute neurodegenerative conditions remains to be brain damage, while inhibition of IL-1 causes remark- ␤ evaluated. Further approaches to modifying IL-1 able neuroprotection. Picomolar quantities of IL-1 include ICE inhibitors, neutralising antibodies or injected into the brain of rodents increase dramati- Ͼ binding proteins, small molecular weight receptor cally ( 100%) infarct volume caused by cerebral antagonists, inhibitors of signal transduction, or more ischaemia or excitotoxins in the rat though IL-1 itself general approaches to inhibit the synthesis and/or is not neurotoxic in normal rodent brain. This effect actions of proinflammatory cytokines or microglial seems to be site-specific, with most potent responses activation. Time and further research will tell if these ␤ occurring after striatal administration of IL-1 which approaches are valid and effective—there is certainly exacerbates cortical as well as local damage. Experi- no lack of interest from academic and clinical sectors. mental inhibition of IL-1 action has been achieved mainly by central or systemic administration of the naturally occurring IL-1 receptor antagonist (IL-1ra). References Ischaemic, excitotoxic and traumatic brain injury 1 Rothwell NJ, Hopkins SJ. Cytokines and the nervous sys- (infarct volume) are reduced by 50–70% in rodents tem II: actions and mechanisms of action. TiNS 1995; 18: treated with IL-1ra, and this effect is accompanied by 130–136. an increased number of surviving neurones and 2 Rothwell NJ (ed). Immune Responses in the Nervous Sys- improved neurological function.3 Attenuation of IL- tem. Bios Scientific: London, 1995. 3 Garcia JH, Lin KF, Relton JK. Interleukin-1 receptor antag- 1␤ action, by administration of neutralising anti- ␤ onist decreases the number of neuronic neurons in rats bodies, or processing of IL-1 (to release the acute with middle cerebral artery occulsion. Am J Pathol 1995; ␤ form) by pharmacological inhibition of interleukin-1 147: 1477–1486. converting enzyme (ICE) activity (required for cleav- 4 Rothwell NJ. Cytokines in Alzheimer’s and other neuro- age of pro-IL-␤) also markedly inhibits ischaemic degenerative diseases. In: Turner JD, Beyreuther K, Theur- Cytokines and acute neurodegeneration NJ Rothwell 121 ing F (eds). Alzheimer’s Disease Ernst Schering Research Correspondence: NJ Rothwell, School of Biological Sciences, Foundation Workshop 17. Springer-Verlag: Berlin, 1996, University of Manchester, 1.124 Stopford Building, Oxford pp 127–146. Ȱ 5 Loddick SA, MacKenzie A, Rothwell NJ. An ICE inhibitor, Rd, Manchester M13 9PT, UK. E-mail: Nancy.Rothwell z-VAD-DCB attenuates ischaemic brain damage in the rat. man.ac.uk NeuroReport 1996; 7: 1465–1468.