Tetrahydrocannabivarin exhibits anticonvulsant effects in a piriform cortical brain slice model of epileptiform activity

S. Weston*, E.M. Williamson*, A. Constanti**, G. Stephens* & B. Whalley* *Reading School of Pharmacy, University of Reading, Whiteknights, Reading, Berks RG5 6AH; **Dept. of Pharmacology, The School of Pharmacy, University of London, 29/39 Brunswick Sq., London WC1N 1AX.

Cannabis has been historically used as an anticonvulsant by epilepsy sufferers as long ago as the 1840s (O'Shaughnessy, 1842), although more recent research has highlighted both pro- (Kalant, 2004) and anti-convulsant (Alger, 2004) effects of cannabinoids, suggesting that pro-/anti-seizure activity may be dependent upon the relative phytocannabinoid content within herbal cannabis preparations (Whalley et al., 2004).

The potential pro-/anti-convulsant activity of one such phytocannabinoid, ∆9-tetrahydrocannabivarin (THCV) (Thomas et al., 2005), was investigated using a Mg2+-free model of epileptiform activity in acute transverse rat (P>40; female; Hampshire (outbred)) piriform cortical (PC) brain slices (Whalley et al., 2005; 2006) and recorded electrophysiologically at room temperature with an extracellular multi-electrode array system (8x8 electrode array). Spontaneous bursts were induced using Mg2+-free Krebs medium (15 min exposure) and bath-applied THCV (5μM in ethanol; final bath ethanol concentration ≤0.001%, 15 min; n=5 for all data; significance by paired t-test; data shown as mean ± s.e.m.) reduced the frequency of bursts (control: 0.03 ± 0.001 Hz; THCV: 0.01 ± 0.001 Hz; P<0.05), and peak-to-peak burst amplitude (control: 124 ± 21μV; THCV: 68 ± 17μV; P<0.05). In addition, THCV reduced both the early negative (N) (control: 201 ± 32μV; THCV: 85 ± 19μV; P<0.05) and late positive (P) (control: 126 ± 32μV; THCV: 17 ± 11μV; P<0.05) wave components of the epileptiform field potential evoked following intrinsic (PC layer II/III) fibre stimulation (4V monopolar) and recorded at the burst focus. Moreover, spontaneous bursting was found to spread from a single recording focus (0.71 μm2) across the whole of the recorded area (2.66 mm2) in control slices, but was limited to an area of 0.27 ± 0.02 mm2 around the focus in the presence of THCV, suggesting an inhibition of seizure propagation. Interestingly, in control medium, THCV (5μM) had no obvious effect upon the evoked early non-NMDA-mediated P-wave (control: 82 ± 21μV; THCV: 91 ± 18μV; P>0.5) and only slightly suppressed the late P wave (control: 107 ± 17μV; THCV: 68 ± 18μV; P<0.1).

These results suggest that THCV had little effect on normal activity in the piriform cortex whilst clearly disrupting the spread of epileptiform activity and thus may act as a novel anticonvulsant component within herbal cannabis.

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THCV was a generous gift from GW Pharmaceuticals.