MECHANISMS OF SECONDARY BRAIN INJURY

The mechanisms which lead to secondary brain damage following transien t ischaemia are incompletely defined. As discussed in this hypothesis article, the events which lead to such damage could encompass (a) a pe rturbed membrane handling of calcium, leading to a slow, gradual incre ase in the free cytosolic calcium concentration (Ca-i(2+)), with subse quent calcium overload of mitochondria, (b) a sustained reduction of p rotein synthesis which, in the long run, deprives cells of enzymes or trophic factors essential to their survival, or (c) the initiation of an inherent program for cell death. Results obtained in ischaemia of b rief to intermediate duration demonstrate that the ultimate cell death is heralded by a reduction in the respiratory capacity of isolated mi tochondria. However, the results fail to demonstrate whether or not su ch a reduction precedes deterioration of the bioenergetic state which then precipitates cell death. Cyclosporin A (CsA) has recently been sh own to dramatically improve the delayed CA1 damage following transient forebrain ischaemia. Since CsA is known to block a deleterious permea bility transition (PT) in mitochondria from several tissues in,respons e to calcium accumulation and oxidative stress, the results on CsA eff ects in forebrain ischaemia support a mitochondrial origin for the del ayed cell death. Furthermore, comparisons with the effects of CsA and alpha-phenyl-N-tert-butyl nitrone (PEN) in thymocytes and other cells undergoing programmed cell death suggest that delayed neuronal damage occurs by a sequence of events akin to those leading to apoptotic cell death. However, whether cell death is apoptotic or necrotic may depen d on the severity of the insult (and its duration). We speculate that the initial ischaemic transient leads to gradual mitochondrial calcium overload, the latter triggering a PT, and apoptotic or necrotic cell death. Since similar results have been obtained in normoglycaemic anim als subjected to ischaemia of intermediate duration, and in animals wi th preischaemic hyperglycaemia, it seems likely that both increased is chaemia duration and hyperglycaemia accelerate damage to mitochondria in the reperfusion period. Recent results obtained in transient focal ischaemia of 2 h duration demonstrate that the free radical spin trap PEN reduces infarct size, even when given 1 or 3 h after the start of reperfusion, thus providing a second window of therapeutic possibility . A major effect of the drug is exerted on the recovery of energy meta bolism of the tissue since it reduces a secondary deterioration in the bioenergetic state, occurring after 2-4 h of reperfusion. At least in part, the spin trap may exert: its effect by reducing microvascular d ysfunction caused by oedema and to adhesion of polymorphonuclear (PMN) leucocytes, which give rise to an inflammatory response mediated by c ytokines, lipid mediators, or free radicals. This contention is suppor ted by the reduction in focal ischaemic damage by antibodies to adhesi on molecules for PMNs. However, it has now been found that the seconda ry deterioration of the bioenergetic state of core and penumbral tissu es are mirrored by corresponding changes in the respiratory functions of isolated mitochondria suggesting that, also in this type of ischaem ia, the mitochondria suffer secondary damage. It is conceivable that a significant fraction of malfunctioning mitochondria emanate from micr ovascular tissue, explaining why antibodies to adhesion molecules miti gate the ischaemic lesions.