Efficacy evaluation of a commercially available MCT enriched therapeutic diet on dogs with idiopathic epilepsy treated with zonisamide: a prospective, randomized, double-blinded, placebo-controlled, crossover dietary preliminary study.

BACKGROUND: Idiopathic epilepsy (IE) is a common, chronic brain dysfunction in dogs. Recently, the effect of feeding a diet enriched with medium-chain triglycerides (MCTs) on seizure frequency has been evaluated in several studies in dogs with IE. However, most dogs with IE in previous studies were treated with phenobarbital as the main antiseizure medication (ASM). In Japan, zonisamide (ZNS) is the most prescribed ASM for dogs with IE. The interaction between ZNS and various nutrients including MCTs and the potential effects on treatment efficacy resulting from combining these therapies have not been previously studied. A prospective, randomized, double-blinded, placebo-controlled, crossover dietary study was conducted. Dogs (n = 7) treated with ZNS were fed either a placebo diet (PL) or Purina ProPlan Veterinary Diet NeuroCare (NC) for 3 months, after which treatments were crossed over and continued for another 3 months. Seizure frequency (seizures/month; sz/m), blood tests including concentrations of ZNS and ß-hydroxybutyric acid, and owner's visual analogue scale score were collected from all dogs for both treatment periods. RESULTS: There was no significant difference in the seizure frequency between PL (2.95 ± 0.80 sz/m) and NC (1.90 ± 0.57 sz/m) during the 6 months of trial. Three of 7 dogs showed ≥ 50% seizure reduction, and 1 of those 3 dogs achieved seizure freedom in NC period. However, 2 of 7 dogs had no changes in epileptic seizure frequency, 2 of 7 dogs had a deterioration in seizure frequency in the NC period. Feeding the MCT diet concurrent with ZNS showed no apparent adverse effects and did not affect ZNS concentration. CONCLUSIONS: This study indicated that the commercially available MCT-enriched diet (NC) can be safely used concurrently with ZNS for dogs with IE.

Identification of molecular determinants for a potent mammalian TRPA1 antagonist by utilizing species differences.

The transient receptor potential A1 (TRPA1) receptor is a member of the TRP family and an excitatory nonselective cation channel. An increasing body of evidence suggests that TRPA1 acts as a nociceptor for various chemicals and physical stimuli. Thus, many TRPA1 antagonists have been developed as analgesic agents. Recently, we found that AP18, a mammalian TRPA1 antagonist, does not inhibit heterologously expressed western clawed frog TRPA1 (fTRPA1). Here, we show that fTRPA1 is also insensitive to A967079, one of the most potent mammalian TRPA1 antagonists. Neither heterologously nor endogenously expressed fTRPA1 was inhibited by A967079 upon activation by TRPA1 agonists. Mutant channel analyses revealed that two specific amino acid residues located within the putative fifth transmembrane domain were involved in the inhibitory action of A967079. Our findings and previous reports based on species differences in the sensitivity to TRPA1 antagonists provide novel insights into the structure-function relationship of TRPA1 and supply useful information in the search for new analgesic medicines targeting TRPA1.

Analysis of transient receptor potential ankyrin 1 (TRPA1) in frogs and lizards illuminates both nociceptive heat and chemical sensitivities and coexpression with TRP vanilloid 1 (TRPV1) in ancestral vertebrates.

Transient receptor potential ankyrin 1 (TRPA1) and TRP vanilloid 1 (V1) perceive noxious temperatures and chemical stimuli and are involved in pain sensation in mammals. Thus, these two channels provide a model for understanding how different genes with similar biological roles may influence the function of one another during the course of evolution. However, the temperature sensitivity of TRPA1 in ancestral vertebrates and its evolutionary path are unknown as its temperature sensitivities vary among different vertebrate species. To elucidate the functional evolution of TRPA1, TRPA1s of the western clawed (WC) frogs and green anole lizards were characterized. WC frog TRPA1 was activated by heat and noxious chemicals that activate mammalian TRPA1. These stimuli also activated native sensory neurons and elicited nocifensive behaviors in WC frogs. Similar to mammals, TRPA1 was functionally co-expressed with TRPV1, another heat- and chemical-sensitive nociceptive receptor, in native sensory neurons of the WC frog. Green anole TRPA1 was also activated by heat and noxious chemical stimulation. These results suggest that TRPA1 was likely a noxious heat and chemical receptor and co-expressed with TRPV1 in the nociceptive sensory neurons of ancestral vertebrates. Conservation of TRPV1 heat sensitivity throughout vertebrate evolution could have changed functional constraints on TRPA1 and influenced the functional evolution of TRPA1 regarding temperature sensitivity, whereas conserving its noxious chemical sensitivity. In addition, our results also demonstrated that two mammalian TRPA1 inhibitors elicited different effect on the TRPA1s of WC frogs and green anoles, which can be utilized to clarify the structural bases for inhibition of TRPA1.