Anticonvulsant Effects of N‐Arachidonoyl‐Serotonin, a Dual Fatty Acid Amide Hydrolase Enzyme and Transient Receptor Potential Vanilloid Type‐1 (TRPV1) Channel Blocker, on Experimental Seizures: The Roles of Cannabinoid CB1 Receptors and TRPV1 Channels

Abstract

Selective blockade of anandamide hydrolysis, through the inhibition of the FAAH enzyme, has anticonvulsant effects, which are mediated by CB1 receptors. Anandamide, however, also activates TRPV1 channels, generally with an opposite outcome on neuronal modulation. Thus, we suggested that the dual FAAH and TRPV1 blockade with N-arachidonoyl-serotonin (AA-5-HT) would be efficacious in inhibiting pentylenetetrazole (PTZ)-induced seizures in mice. We also investigated the contribution of CB1 activation and TRPV1 blockade to the overt effect of AA-5-HT. In the first experiment, injection of AA-5-HT (0.3-3.0 mg/kg) delayed the onset and reduced the duration of PTZ (60 mg)-induced seizures in mice. These effects were reversed by pre-treatment with the CB1 antagonist, AM251 (1.0-3.0 mg/kg). Finally, we observed that administration of the selective TRPV1 antagonist, SB366791 (0.1-1 mg/kg), did not entirely mimic AA-5-HT effects. In conclusion, AA-5-HT alleviates seizures in mice, an effect inhibited by CB1 antagonism, but not completely mimicked by TRPV1 blockage, indicating that the overall effect of AA-5-HT seems to depend mainly on CB1 receptors. This may represent a new strategy for the development of drugs against seizures, epilepsies and related syndromes.The endocannabinoid arachidonoyl ethanolamide (anandamide) is involved in the modulation of several neurophysiological processes, including nociception, memory, pain and convulsive seizures [1,2]. In the nervous system, anandamide is synthesized and released as a neurotransmitter from membrane lipids [3]. Its actions are terminated by hydrolysis mediated by fatty acid amide hydrolase (FAAH) [4], an enzyme highly expressed in several brain regions [5]. Accordingly, enhancement of anandamide signalling can be achieved by selective inhibition of FAAH activity [6].The primary target for anandamide is the type 1 cannabinoid (CB1) receptor, a metabotropic receptor mainly coupled to a Gi protein [7]. Another proposed target is the transient receptor potential vanilloid type-1 channel (TRPV1) [8][9][10][11]. This receptor is activated by heat (>43°C), low pH and the pungent ingredient of hot chilli peppers, capsaicin, as well as anandamide [8,12]. Indeed, TRPV1 and CB1 are co-expressed in several brain regions, including the hypothalamus, cerebellum, cerebral cortex, striatum, midbrain, hippocampus and substantia nigra, although they may have opposite roles in modulating neural activity [13][14][15][16]. For instance, in contrast to CB1 receptor, TRPV1 activation promotes calcium influx, firing rate and glutamate release, facilitating long-term potentiation and suppressing long-term depression. Such changes could be associated with the enhancement of synaptic efficiency and may be important in epileptogenesis [17,18].Anticonvulsant properties mediated through the activation of cannabinoid CB1 receptors have been observed in different experimental seizure models, in which anandamide is produced on-demand to restrain excitotoxicity [19][20][21]. Recently, it has be...

Cannabidiol, a Cannabis sativa constituent, inhibits cocaine-induced seizures in mice: Possible role of the mTOR pathway and reduction in glutamate release

“…The CB 1 receptor antagonist, AM251 (1 and 3 mg/kg; Cayman Chemical, USA), and the CB 2 antagonist, AM630 (2 and 4 mg/kg; Cayman Chemical, USA) were dissolved in cremophor-ethanol-saline at the proportion of 1:1:18. These doses were selected based on previous studies(Rizzo et al, 2014;Vilela et al, 2014). The mTOR inhibitor, rapamycin (1 or 5 mg/kg; LC-Laboratories, USA), was dissolved in vehicle containing 4% ethanol, 4% PEG400 and 2% Tween 80.…”

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Anti-Inflammatory and Antioxidant Actions of <b><i>N</i></b>-Arachidonoyl Serotonin in RAW264.7 Cells

“…It prevented the convulsion in mice administered with pentylenetetrazole [27] , enhanced anxiolytic behavior in the elevated plus maze (EPM) in mice at basolateral amygdale [28] , reduced carrageenan-induced hyperalgesia in mice [29] and decreased anxiety-like behavior in EPM [30] . Recently, NA-5HT was observed to possess anti-allergic and anti-inflammatory actions in mast cells [13,14] .…”