Protective Effect of L‐carnitine In Ammonia‐precipitated Encephalopathy In the Portacaval Shunted Rat (original) (raw)

as gastrointestinal bleeding, constipation, or sedative use. 1 L-carnitine administration prevents the neurological Symptoms of PSE are generally reversible suggesting a metasymptoms of acute ammonia toxicity. To further evalubolic cause. ate its efficacy in the prevention of hepatic encephalopa-Of the possible neurotoxins implicated in PSE, ammonia thy in hyperammonemic conditions, L-carnitine (16 was the first to be incriminated 2 and is still considered a mmol/kg, intraperitoneally [ip]) was administered 1 leading candidate. 2-5 Neurochemical mechanisms so far prohour before ammonium acetate (NH 4 OAc) (8.5 mmol/kg, posed to explain the neurotoxic effects of ammonia include subcutaneously) to portacaval shunted (PCS) rats. Ceredirect effects on excitatory and inhibitory neurotransmisbrospinal fluid (CSF) ammonia, lactate, and amino acid sion 6,7 and on neuron-astrocytic metabolic trafficking 8 as well levels were measured in relation to deteriorating neuroas effects mediated via glutamine accumulation in brain. 9 logical status in these animals. None of 35 L-carnitine-If sufficiently prolonged or severe, ammonia may also have treated animals showed neurological deterioration after adverse effects on brain energy metabolism. 10,11 In this latter NH 4 OAC administration compared with saline-treated regard, there is evidence to suggest disruption of the malatecontrols; the latter manifested severe encephalopathy aspartate shuttle in brain in experimental PSE. 11 In addition, progressing through loss of righting reflex to coma. Surresults of in vitro studies suggest inhibition of the tricarboxvival rate was 100% in the L-carnitine-treated group ylic acid cycle enzyme a-ketoglutarate dehydrogenase compared with 5% in saline-treated controls. Following (aKGDH) by pathophysiological concentrations of ammonia 12 NH 4 OAC administration to PCS rats, CSF ammonia inand thus the potential for impaired cerebral energy metabocreased to 0.93 { 0.15 mmol/L and 1.24 { 0.15 mmol/L at lism. precoma and coma stages of encephalopathy (P õ .01) Few treatments of hyperammonemic syndromes are specifrespectively. Treatment with L-carnitine reduced CSF ically designed at counteracting the molecular actions of amammonia at both precoma and coma stages; the timemonia. It has been reported that L-carnitine administration course of this protective effect paralleled blood and CSF to mice 1 hour before a lethal injection of ammonium acetate L-carnitine accumulation. CSF alanine and lactate in-(NH 4 OAc) prevents both symptoms of ammonia toxicity and creases following NH 4 OAC administration to PCS rats death. 13 It was suggested that L-carnitine led to decreased were significantly attenuated following L-carnitine blood and brain ammonia in part by induction of ureagenesis. treatment. However, L-carnitine treatment did not lead Subsequently, the ammonia-lowering effects of L-carnitine to significant reductions in plasma ammonia nor CSF or were confirmed in portacaval shunted rats. 14 brain glutamine in these animals. These findings show Construction of an end-to-side portocaval anastomosis in the therapeutic efficacy of L-carnitine in ammonia-prethe rat is currently the most widely used animal model prepacipitated coma in PCS rats and suggest that this protecration to study metabolic and neurochemical effects of chronitive effect is centrally mediated involving improved cally impaired liver function and concomitant chronic hypermitochondrial respiration. L-carnitine could be of theraammonemia. Four weeks after anastomosis, rats show severe peutic benefit in the prevention of hepatic encephalopaliver atrophy and neurological signs of encephalopathy such thy precipitated by ammoniagenic conditions in humans as diminished spontaneous locomotor activity 15 and altered with chronic liver disease. (HEPATOLOGY 1997;25:551day-night 16 and circadian 17 rhythms. The administration of 556.) ammonium acetate to shunted rats results in severe signs of encephalopathy progressing through loss of righting reflex Portal-systemic encephalopathy (PSE) is a common neuroand coma. The present study was undertaken to assess the psychiatric disorder resulting from chronic liver failure. Clinefficacy of L-carnitine in the prevention of severe encephalopical features of PSE episodes include impaired mental funcathy caused by ammonium acetate treatment in portacaval tion, neurological disturbances such as asterixis or ''flapping shunted rats. To avoid the potential dilution factor of ammotremor,'' and altered states of consciousness progressing nia by L-carnitine in the peritoneal cavity 18 two independent through stupor and coma. Multiple PSE episodes are common routes of administration of ammonium acetate and L-carniand are frequently associated with precipitating factors such tine, respectively, were chosen.