Diacylglycerols and Arachidonic Acid in the Molecular Pathogenesis of Brain Injury

Abstract

Stimulation or injury promotes an accumulation of free fatty acids (FFA) and diacylglycerols in the central nervous system (Bazan, 1970, 1971; Bazan and Rako-wski, 1970; Bazan et al., 1971; Aveldano and Bazan 1975a, b, 1979; Bazan, 1976). The accumulated lipids are potentially harmful to excitable membranes by mechanisms such as FFA inhibition of membrane-bound enzymes (Rhoads et al., 1983) and lipid peroxidation (Yoshida et al., 1982). The accumulation of FFA following a single electroconvulsive shock (ECS) is transient, returning to normal levels within 5 min after the shock (Bazan and Rakowski, 1970). Similarly, the FFA increase in gerbil brain due to ischemia induced by bilateral carotid occlusion can be reversed to normal levels after reperfusion (Yoshida et al., 1980, Bhakoo et al., 1984). In the case of prolonged ischemia or during bicuculline-induced status epilepticus, the accumulation of FFA and DAG continues to rise and may lead to irreversible brain damage (Aveldano and Bazan, 1975a, b; DeMedio et al., 1980; Shiu et al., 1983; Tang and Sun, 1982, 1985; Rodriguez de Turco et al., 1983). Irreversible damage may occur because of selective degradation of functionally critical lipid classes or molecular species of lipids (e. g. polyphosphoinositides) in synaptic membranes and/or other cell membranes, such as mitochondria (Bazan et al., 1971; Bazan, 1976). In brain, accumulation of DAG and FFA (especially polyunsaturates) as a result of catabolism of polyphosphoinositides, may disturb interneuronal communication by altering levels of secondary messengers (DAG itself and water-soluble inositol polyphosphates) and the activity of protein kinase C. Protein kinase C in brain, which can be activated by polyunsaturated fatty acids (Murakami and Routtenberg, 1985) and unsaturated DAG (Nishizuka et al., 1984a), appears to play a critical role in stimulus-secretion coupling (Kawahara et al., 1980; Wooten and Wrenn, 1984; Putney et al., 1984).