Abstract
The medium chain triglyceride (MCT) ketogenic diet is a major treatment for drug resistant epilepsy but is problematic, particularly in adults, because of poor tolerability. Branched derivatives of octanoic acid, a medium chain fat provided in the diet have been suggested as potential new treatments for drug-resistant epilepsy, but the structural basis of this functionality not been determined. Here we investigate structural variants of branched medium chain fatty acids as new seizure-control treatments. We initially employ a series of methyl-branched octanoic acid derivatives, and using the GABA(A) receptor antagonist, pentelenetetrazol (PTZ), to induce seizure-like activity in rat hippocampal slices, we show a strong, branch-point specific activity that improves upon the related epilepsy treatment, valproic acid. Using low Mg2+ conditions to induce glutamate excitotoxicity in rat primary hippocampal neuronal cultures for the assessment of neuroprotection, we also show an identical structural dependence to that for seizure control suggesting a related mechanism of action for these compounds in both seizure control and neuroprotection. In contrast, the effect of these compounds on histone deacetylase (HDAC) inhibition, associated with teratogenicity, show no correlation with therapeutic efficacy. Furthermore, small structural modifications of the starting compounds provide active compounds without HDAC inhibitory effects. Finally, using multiple in vivo seizure models, we identify potent lead candidates for the treatment of epilepsy. This study therefore identifies a novel family of fatty acids, related to the MCT ketogenic diet, that show promise as new treatments for epilepsy control and, possibly, other MCT ketogenic diet-responding conditions such as Alzheimer's disease.
- animal models
- anticonvulsants
- antiepileptics
- cell death
- drug design
- drug development
- drug discovery
- drug efficacy
- epilepsy
- seizures
- The American Society for Pharmacology and Experimental Therapeutics