Carnitine pretreatment can partially change the excitability of the immature nervous tissue (original) (raw)
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Brain and Development, 2005
Glutamate mediated intracellular calcium accumulation and free radical generation are thought to be major mechanisms that contribute to cell death in hypoxic-ischemic brain injury. For this reason, various glutamate receptor antagonists and antioxidants have been investigated for their therapeutic potential. To assess whether L-carnitine, a possible antioxidant, is able to prevent glutamate-and kainic acid (KA)induced neurotoxicity. Glutamate (10 K7 M) and one of its receptor agonists, KA (10 K4 M) were administered to cerebellar granular cell cultures that were prepared from 1-day-old Sprague-Dawley rats. The neuroprotective effect of L-carnitine was examined. L-carnitine at doses of 10 K6 , 10 K5 , 10 K4 , 10 K3 M was applied to culture flasks. L-carnitine at doses of 10 K4 and 10 K3 M significantly blocked glutamateinduced neurotoxicity. 10 K4 M dose of L-carnitine proved to be more effective than 10 K3 M. L-carnitine also blocked KA-induced neurotoxicity only at the dose of 10 K4 M. 10 K4 M L-carnitine, the most effective dose in both glutamate-and KA-induced neurotoxicity, decreased glutamate-induced neuronal cell death from 36.14G2.95% to 17.59G2.25%; (P!0.001) and KA-induced neuronal cell death from 21.4G0.41 to 13.4G1.38%; (P!0.001). The present study demonstrates that L-carnitine protects against glutamate-and KA-induced neurotoxicity. Protective effect of L-carnitine may result from its antioxidant activity because free radical generation is a common result in either glutamate-or KA-induced neurotoxicity. L-carnitine merits further investigation as a therapeutic option in hypoxic-ischemic brain injury of newborn. q
Hepatology, 1997
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.
Neuroscience Letters, 2004
A plant and fungal toxin, 3-NPA, acts as an inhibitor of mitochondrial function via irreversible inactivation of the mitochondrial inner membrane enzyme, succinate dehydrogenase (SDH). Inhibition of SDH disturbs electron transport and leads to cellular energy deficits and neuronal injury. We have shown that pretreatment with l-carnitine, while not significantly attenuating SDH inhibition, prevented hypothermia and oxidative stress-associated increased activity of free radical-scavenging enzymes. Here, a neurohistological method was applied to examine the effect of carnitine pretreatment against 3-NPA-induced neurotoxicity. Twenty adult male Sprague-Dawley rats were randomly divided into two groups (n = 10/group). Rats in the first group were injected twice with 3-NPA at 30 mg/kg s.c., 2 days apart, and the second group of animals received l-carnitine pretreatment at 100 mg/kg 30-40 min before 3-NPA administration. Rats in both groups were perfused 7 days later and their brains harvested. Degenerating neurons were identified and localized via the fluorescent marker Fluoro-Jade B. In the three animals that survived 3-NPA dosing, one exhibited no pathology, one exhibited moderate unilateral damage to the striatum, and the third exhibited extensive bilateral neuronal degeneration in multiple forebrain regions. In the seven surviving animals that received l-carnitine prior to 3-NPA insult, six exhibited no lesions, while one exhibited a modest unilateral lesion in the striatum. It appears that l-carnitine is protective against 3-NPA-induced toxicity, as reflected by both reduced mortality and significantly reduced neuronal degeneration.
Carnitine deficiency in epileptic children treated with a diversity of anti-epileptic regimens
The Egyptian journal of neurology, psychiatry and neurosurgery, 2018
Carnitine deficiency is relatively common in epileptic patients. The risk factors reported include the combination of valproic acid with other antiepileptic drugs (AEDs), young age, multiple neurologic disabilities, non-ambulatory status, and being underweight. To study the level of carnitine deficiency and its associated risk factors among a group of children with idiopathic epilepsy treated with different AEDs. Fifty children with idiopathic epilepsy and 40 age-matched controls were enrolled. For all, serum carnitine level was measured by enzyme-linked immune sorbent assay (ELISA). The mean carnitine level was lower in cases compared to controls ( = 0.04). Patients receiving monotherapy treatment had a high percentage of carnitine deficiency compared to controls ( = 0.04). Patients receiving valproate with other AEDs had a lower level of carnitine compared to controls ( = 0.03). The age of the patients, the duration of treatment, and the doses of different AEDs were not risk facto...
Brain sciences, 2018
l-Carnitine is a unique nutritional supplement for athletes that has been recently studied as a potential treatment for certain neuropsychiatric disorders. However, its efficacy in seizure control has not been investigated. Sprague Dawley rats were randomly assigned to receive either saline (Sal) (negative control) or pentylenetetrazole (PTZ) 40 mg/kg i.p. × 3 times/week × 3 weeks. The PTZ group was further subdivided into two groups, the first received oral l-carnitine (l-Car) (100 mg/kg/day × 4 weeks) (PTZ + l-Car), while the second group received saline (PTZ + Sal). Daily identification and quantification of seizure scores, time to the first seizure and the duration of seizures were performed in each animal. Molecular oxidative markers were examined in the animal brains. l-Car treatment was associated with marked reduction in seizure score (= 0.0002) that was indicated as early as Day 2 of treatment and continued throughout treatment duration. Furthermore, l-Car significantly pro...
The role of L-carnitine in the brain aging
Pharmakeftiki, 2009
Carnitine is an important compound of cellular metabolism and it is essential for b-oxidation of lipid acids. In neural system, although b-oxidation is not the main source of energy, carnitine is involved in the regulation of energy production and calorie intake, the latter via the hypothalamus, as well as indirectly in synaptic neurotransmission. Since the above cellular processes are modified during brain aging, we aimed to review the literature on the role of carnitine in brain aging. Particular emphasis is given on the mechanisms of antioxidative action of carnitine in brain, as well as its association with cholinergic and dopaminergic system along with other various neural membrane receptors, such as the NMDA, calcium or nerve growth factor (NGF) receptors. In addition, the connection of carnitine with mechanisms of protection against cellular stress and particularly its relation with heat shock proteins (HSP), ionic channels and sodium pump, is also reviewed.
Effect of L-carnitine on postischemic inhibition of protein synthesis in the rat brain
General Physiology and Biophysics, 2009
The purpose of this study was to investigate effects of carnitine administration on protein synthesis recovery after transient cerebral ischemia. Rats received L-carnitine in two doses of 16 mmol/kg i.p. 15 min before ischemia and just on the onset of reperfusion. Transient forebrain ischemia was induced by 4-vessel occlusion for 15 min, followed by 30 min or 7 days of reperfusion. Protein synthesis rate, reinitiation ability and neurodegeneration in the frontal cortex and hippocampus were measured by the incorporation of radioactively labelled leucine into polypeptide chains in postmitochondrial supernatants and by Fluoro-Jade B staining. A protective effect was observed, on protein synthesis as well as the number of surviving neurons, in the L-carnitine-treated groups. Our results indicate that L-carnitine can exert a protective effect in the development of reperfusion-induced injury. L-carnitine significantly reduced the ischemia/reperfusion-induced inhibition of translation and neurodegeneration in the neocortex as well as in the highly sensitive hippocampus and dorsolateral striatum. We expect that the ability of L-carnitine to keep translational machinery on facilitates efficacy of postischemic remodulation of gene expression.
Neuroscience Letters, 1997
The effect of acetyl-l-carnitine (ALC) on behavioral deficits following neonatal anoxia (N 2 100% for 25 min at 30 h after birth) was studied in the rat. Transient hyperactivity at P20-P45 postnatal days and permanent spatial memory deficits were shown by anoxic rats. A chronic ALC treatment (50 mg/kg per die injected intraperitoneally from P2, after anoxia, to P60) significantly reduced the transient increase in sniffing, rearing and locomotory activity of anoxic rats, but, mostly, ameliorated the spatial memory performances in a maze at P30-P40 and in a water maze at P50-P60. No behavioral changes were seen in ALC-treated animals that received sham-exposure at birth. On the basis of these results, the use of ALC for the treatment of perinatal asphyctic insults in children is suggested.
l-Carnitine Supplementation in Childhood Epilepsy: Current Perspectives
Epilepsia, 1998
In November 1996, a panel of pediatric neurologists met to update the consensus statement issued in 1989 by a panel of neurologists and metabolic experts on L-carnitine supplementation in childhood epilepsy. The panelists agreed that intravenous L-carnitine supplementation is clearly indicated for valproate (VPA)-induced hepatotoxicity, overdose, and other acute metabolic crises associated with carnitine deficiency. Oral supplementation is clearly indicated for the primary plasmalemmal carnitine transporter defect. The panelists concurred that oral L-carnitine supplementation is strongly suggested for the following groups as we& patients with certain In August of 1989, the Pediatric Neurology Advisory Committee (on Carnitine and Seizures) to Sigma-Tau Pharmaceuticals issued a consensus statement on the subject of L-carnitine supplementation for patients taking valproate (VPA) for-epilepsy. The Committee recommended the prophylactic administration of L-carnitine to all children younger than 2 years who were taking VPA and the selective administration of L-carnitine to all children who had evidence of carnitine deficiency. Carnitine deficiency was defined as a plasma free concentration of S20 pM at an age older than 1 week after term or a plasma esterified-to-free ratio of 30.4 at an age older than 1 week after term. Many neurologists still subscribe