Canine and Feline Epilepsy. Luisa De Risio
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responsible for the rat glial glutamate transporter (GLT) is reduced in several brain regions in epilepsy-prone rats (Meldrum et al., 1999). GLT ‘knockout’ mice have been bred to provide homozygous mice, in which the GLT protein is not detected. In such mutant mice, glutamate uptake in cortical synaptosomes is 5.8% compared with the wild-type (Meldrum et al., 1999). The mutant mice show spontaneous seizures, with wild running and tonic extension, which is frequently fatal. In chronic seizure models (kindled seizures, spontaneous seizures and genetically epilepsy-prone rats), there are numerous reports of increases in extracellular glutamate during seizures (Meldrum et al., 1999). This strongly suggests that in these chronic models there are sustained functional alterations in mechanisms relating to the synaptic release of glutamate or its transport. GLT-1 astrocytic expression was reduced in four Shetland sheepdogs with IE (Morita et al., 2005). In these dogs it was suggested that decreased expression of the transporter might be related to development of status epilepticus.
There is not as yet any genetically determined epilepsy syndrome occurring spontaneously in man or mouse that can be ascribed to a primary gene defect involving a glutamate receptor or transporter.
Targets for treatment
In animal models of epilepsy, antagonists acting at NMDA receptors, AMPA receptors or at Group I metabotropic receptors have potent anticonvulsant actions (Meldrum and Chapman, 1999; Rogawski and Donevan, 1999; Chapman, 2000; Moldrich et al., 2003).
NMDA receptor antagonists have been successful in stopping the maintenance phase of self-sustaining status epilepticus (SE) in rats, which suggests that these compounds may have a promising role in the treatment of unrelenting seizure activity such as SE (Mazarati and Wasterlain, 1999). Studies with selective AMPA receptor antagonists have indicated that AMPA receptors are potentially promising anticonvulsant drug targets, but at present this is uncertain (Rogawski and Donevan, 1999).
In genetic mouse models, mGlu1/5 antagonists and mGlu2/3 agonists are effective against absence seizures. Thus, antagonists at Group I mGlu receptors and agonists at Groups II and III mGlu receptors are potential anti-epileptic agents, but their clinical usefulness will depend on their acute and chronic side-effects (Moldrich et al., 2003). Potential also exists for combining mGlu receptor ligands with other glutamatergic and non-glutamatergic agents to produce an enhanced anticonvulsant effect (Moldrich et al., 2003).
The Veterinary Perspective
Idiopathic epilepsy (see Chapter 6) is the most common cause of seizures in dogs (Podell and Hadjiconstantinou, 1997). Low levels of GABA and high levels of glutamate have been detected in the cerebrospinal fluid of epileptic dogs independent of time relation to recent seizure activity (Podell and Hadjiconstantinou, 1997). The glutamate elevations are not related whether the seizures were focal or generalized in character (Podell and Hadjiconstantinou, 1997). These findings may indicate the brains of epileptic dogs are under a state of chronic over-excitation. Although a separate study found that lower CSF GABA concentration was associated with a reduced response to phenobarbital therapy in dogs, there was no association between CSF glutamate and response to this therapy (Podell and Hadjiconstantinou, 1999). However, a negative association was found between CSF glutamate:GABA ratio and response to phenobarbital therapy (Podell and Hadjiconstantinou, 1999). Therefore glutamate-mediated mechanisms may be useful targets for anticonvulsant therapy in dogs. Intracerebral microdialysis was used to demonstrate elevation of extracellular levels of glutamate in four Shetland sheep-dogs with IE, suggesting an important role in the occurrence of seizure activity (Morita et al., 2005).
Gabapentin (see Chapter 17), a relatively new human anticonvulsant, has been evaluated in dogs refractory to phenobarbitone and potassium bromide with an approximate 50% success rate.
Gabapentin has been shown to modestly decrease glutamate levels in the brain (Errante and Petroff, 2003). Another new anticonvulsant, topiramate (see Chapter 19), produces its antiepileptic effect by several mechanisms, one of which is inhibition of kainite-mediated glutamate receptors (Angehagen et al., 2003a). This drug has also been demonstrated to protect neurons from excitotoxic levels of glutamate, potentially preventing brain damage during seizure activity (Angehagen et al., 2003b).
Catecholamines
Abnormalities of CNS catecholamines have been reported in several genetic models of epilepsy. In the spontaneous epileptic rat, dopamine was decreased in the caudate nucleus whereas noradrenaline was increased in the midbrain and brainstem (Hara et al., 1993). Decreased levels of dopamine have been found in epileptic foci of epilepsy patients (Mori et al., 1987). In animal models of absence epilepsy, seizures are exacerbated by dopamine antagonists while alleviated by dopamine agonists (Snead, 1995). These results suggest that decreased dopamine facilitates appearance of seizures by lowering the threshold triggering such seizures. Tottering mice have an absence-like syndrome that is characterized by episodes of behavioural arrest associated with 6 to 7 Hz cortical SW EEG discharges. Selective destruction of the ascending noradrenergic system at birth prevents the onset of the syndrome. Therefore, it has been suggested that the syndrome is caused by a noradrenergic hyperinnervation of the forebrain (Engelborghs et al., 2000). Recent data indicate that the serotonergic system regulates epileptiform activity in a genetic rat model of absence epilepsy as intraperitoneal or intracerebroventricular administration of 8- OHDPAT caused marked and dose-dependent increases in number and duration of discharges (Gerber et al., 1998).
Opioid peptides
In experimental studies, opioids and opioid peptides had both convulsant and anticonvulsant properties (Engelborghs et al., 2000). Kappa agonists suppress electrical discharges in an animal model of absence epilepsy (Przewlocka et al., 1995). Peptides with a μ-agonist action induce hippocampal or limbic seizures when administered intraventricularly possibly due to inhibition of inhibiting interneurons. In patients with complex partial seizures, PET studies pointed out that μ-receptor density is increased in the temporal cortex (Mayberg et al., 1991).
Inflammatory Mechanisms Underlying Epilepsy
Over the past 10 years an increasing body of clinical and experimental evidence has provided strong support to the hypothesis that inflammatory processes within the brain might constitute a common and crucial mechanism in the pathophysiology of seizures and epilepsy (Vezzani et al., 2011). The first insights into the potential role of inflammation in human epilepsy were derived from clinical evidence indicating that steroids and other anti-inflammatory treatments displayed anticonvulsant activity in some drug-resistant epilepsies (Wirrell et al., 2005; Wheless et al., 2007). Additional evidence came from febrile seizures in people, which always coincide with, and are often caused by, a rise in the levels of pro-inflammatory agents (Dube et al., 2007). Evidence of immune system activation in some patients with seizure disorders, the high incidence of seizures in autoimmune diseases, and the discovery of limbic encephalitis as a cause of epilepsy led to the suggestion that immune and inflammatory mechanisms have roles in some forms of epilepsy (Aarli, 2000; Bien et al., 2007; Vincent and Bien, 2008; Vezzani et al., 2011).
Evidence is emerging that inflammation might be a consequence as well as a cause of epilepsy. Several inflammatory mediators have been detected in surgically resected brain tissue from human patients with refractory epilepsies, including temporal lobe epilepsy (TLE) and cortical dysplasia-related epilepsy (Choi et al., 2009; Vezzani et al., 2011). The finding that brain inflammation occurred in epilepsies that were not classically linked to immunological dysfunction highlighted the possibility that chronic inflammation might be intrinsic to some epilepsies, irrespective of the initial insult or cause, rather than being only a consequence of a specific underlying inflammatory or autoimmune aetiology. The mounting evidence