Читать книгу Canine and Feline Epilepsy - Luisa De Risio - Страница 58

Drug-target hypothesis

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Based on the drug target hypothesis, reduced sensitivity of drug targets such as receptors or ion channels to AEDs is a key cellular mechanism that may cause drug resistance. This hypothesis is based on findings that show that in the hippocampus of human patients with pharmacoresistant temporal lobe epilepsy, the use-dependent inhibition of sodium channels by carbamazepine is lost. This finding did not extend to lamotrigine, which has a pharmacologic action similar to that of carbamazepine (Remy et al., 2003). Polymorphisms in the sodium channel encoding gene SCN2A were found in humans to be responsible for AEDs acting on the sodium channel, but also for other non-sodium channel targeted AEDs (Kwan et al., 2008). As aforementioned, Kennerly et al. (2009) showed that PB non-responders also had changes in the SCN2A gene when compared to PB responders. In addition, two other genes encoding ion channels (KCNQ3 and GABRA2) were affected (Armijo et al., 2005). In a rodent model for pharmacoresistant epilepsy it was demonstrated that there was a shift from GABAA diazepam-sensitive to GABAA diazepam-insensitive receptors in the hippocampus of PB non-responders (Volk et al., 2006). In the same model a significant loss of neurons in the CA1, CA3c/CA4 and dentate hilus of non-responders was found. This could lead to altered network properties, which could be responsible for refractoriness. In human medicine, altered network properties are well recognized in patients with hippocampal sclerosis. Hippocampal sclerosis has been associated with refractoriness to AEDs (Kwan et al., 2011). In dogs, the hippocampus is also involved in seizure propagation, which can result in MRI changes (Kuwabara et al., 2010). Such MRI abnormalities have not been associated with changes in seizure frequency or length in dogs but hippocampal changes visible on MRI are often associated with AED therapy failure in cats (Fatzer et al., 2000; Brini et al., 2004; Schmied et al., 2008).

A wealth of literature on human epilepsy cites evidence of autoantibodies to ion channels (GABAB receptors, Lancaster et al., 2010; NMDA-receptors, Dalmau et al., 2008; calcium channels, McKnight et al., 2005; voltage-gated potassium channels, McKnight et al., 2005). Interestingly, it also appears that cats with hippocampal changes develop autoanti-bodies to voltage-gated potassium channels (Pakozdy et al., 2013). These patients rarely respond to standard AED and in human medicine immunomodulatory treatment has been trialled with variable results (Vincent et al., 2010). Other proposed cellular patho-mechanisms of pharmacoresistant epilepsy that have been suggested include electrical coupling via gap junctions in neurons and glial cells (Voss et al., 2009) and mitochondrial oxidative stress and dysfunction (Waldbaum and Patel, 2010).

Canine and Feline Epilepsy

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