The effect of several antiepileptic treatments on the fatty acid metabolism of Sprague-Dawley rats

Abstract

Treatments for epilepsy encompass a wide range of drugs and dietary supplements and understanding their mechanisms of action is important for effective clinical use. Many structures and processes are involved in the development of a seizure, including neurons, ion channels, receptors, glia, as well as inhibitory and excitatory synapses. Antiepileptic drugs are designed to modify these processes to favour inhibition over excitation in order to stop or prevent seizure. Valproate and carbamazepine are two widely used antiepileptic drugs lthough the chemical structures differ from each other. Acetyl-L-carnitine is a dietary supplement, which assists in fatty acid transportation into the mitochondria. Carnosine is a potential antiepileptic drug that could inhibit seizures through the histaminergic system. The ketogenic diet is a treatment generally used to treat refractory epilepsy. Based on a study by KrOger (2006), who reported increased plasma omega-3-fatty acid levels in epileptic patients treated with carbamazepine or valproate, it was hypothesized that aforementioned drugs could mimic the effects of the ketogenic diet on fatty acid metabolism. The study reported in this dissertation was designed to assess the effect of several anti-epileptic treatments on fatty acid metabolism as monitored by urinary excretion of acylcarnitines, glycine conjugates and glycine. Six groups of male Sprague Dawley rats (n = 10, for each group) were respectively treated with valproate, carbamazepine, carnosine, acetyl-L-carnitine, and a ketogenic diet. The sixth group served as a control. Rats were treated for 28 days, decapitated, and blood and urine samples were collected. For the determination of glycine conjugates and glycine, a standardised method, employing gas chromatography-mass spectrometry (GC/MS), was used. Acylcarnitines was determined using isotope-dilution tandem mass spectrometry (LC-MS/MS). The ketogenic diet resulted in slower body mass gain, as well as increased urinary long chain fatty acylcarnitines (p < 0.001), dicarboxylic fatty acylcarnitines (p < 0.001), acetylcarnitine (p < 0.001), free carnitine (p < 0.001) and 3-hydroxybutyrate-carnitine (p < 0.001) excretion. Valproate, carbamazepine and carnosine treatments did not cause in any statistically significant effects on the parameters of fatty acid metabolism as mentioned above. The data indicate that aforementioned anticonvulsant drugs do not exert their anticonvulsant effects by mechanisms similar to that of the ketogenic diet. Rats treated with acetyl-L-carnitine demonstrated increased urinary acylcarnitine (p < 0.001), carnitine (p < 0.001) and 3-hydroxybutyrate-carnitine (p < 0.001) excretion, suggesting that acylcarnitine may be an effective detoxifying agent for patients suffering from medium-chain acyl-CoA dehydrogenase deficiency (MCADD).