Anticonvulsant mechanisms of piperine, a piperidine alkaloid

Figures & data

Table 1. PASS predicted activity score of piperine

Pa	Pi	Activities
0.906	0.009	Membrane integrity agonist
0.832	0.011	Neuroprotector
0.814	0.004	Neurotransmitter uptake inhibitor
0.740	0.004	Sigma receptor agonist
0.700	0.047	Depression
0.322	0.040	Sigma 1 receptor agonist
0.423	0.203	Nootropic
0.372	0.160	5 HT uptake stimulant
0.181	0.021	Nav1.8 sodium channel antagonist
0.281	0.132	GABA transporter 2 inhibitor
0.291	0.173	Dementia treatment
0.179	0.078	Neurodegenerative diseases treatment
0.069	0.009	GABA uptake inhibitor
0.079	0.030	Calcium channel T-type antagonist
0.213	0.201	Anticonvulsant
0.145	0.139	GABA C receptor agonist
0.104	0.099	Calcium channel antagonist
0.038	0.034	Kainate receptor antagonist

Table 2. Effects of piperine on pentylenetetrazole induced seizures

Treatment	Dose (mg/kg)	Onset of myoclonic jerks (min)	Onset of tonic clonic convulsions (min)	% Mortality
Vehicle	10 ml	1.05 ± 0.21	1.79 ± 0.32	100
Diazepam	5	60 ± 0	60 ± 0	0
Piperine	5	4.77 ± 0.82	12.35 ± 3.04	100
	10	18.2 ± 1.35	47.6 ± 5.27	40
	20	7.992 ± 0.23	21.71 ± 0.95	100

Significant as compared to saline at ** p < 0.01, *** p < 0.001

Table 3. Effect of piperine on maximal electroshock-induced seizures

Treatment	Dose (mg/kg)	Duration of hind limb extension (s)	% mortality
Vehicle	10 ml	18.21 ± 0.42	100
Phenytoin	30	0 ± 0	0
Piperine	5	15.47 ± 2.30	20
	10	10.25 ± 0.41	0
	20	6.43 ± 0.61	0

Significant as compared to saline at * p < 0.05

Table 4. Effect of piperine in different chemoconvulsant models

Treatments		Onset of Convulsions (s)	% protection against seizures	% protection against mortality
NMDA(0.31 µg/mouse)	Vehicle	3.50 ± 0.35	0	0
	PIP 20 mg/kg	5.75 ± 1.25	0	0
Picrotoxin(3.5 mg/kg)	Vehicle	229.80 ± 10.20	0	0
	PIP 20 mg/kg	1134.60 ± 147.60	0	0
Bicuculline(5 mg/kg)	Vehicle	132.20 ± 17.40	0	0
	PIP 20 mg/kg	145.20 ± 4.20	0	0
BAY K(37.5 µg/mice)	Vehicle	6.92 ± 0.25	0	17
	PIP 20 mg/kg	1800.00 ± 0.00	100	100
Strychnine(2 mg/kg)	Vehicle	182.40 ± 7.80	0	0
	PIP 20 mg/kg	879.60 ± 25.80	0	0

Significant as compared to vehicle *** p < 0.001

Figure 1. Effect of piperine on GABA and serotonin levels. (A) The bar chart depicts percentage change in GABA level in cortex and hippocampus and vehicle treated animals at different doses (in mg/kg) of piperine. (B) The bar chart depicts percentage change in serotonin levels in cortex and hippocampus at various doses (in mg/kg) of piperine. Error bars are standard errors, the asterisks denote statistical significance (p < 0.05) relative to vehicle.

Figure 2. Characterization of electrophysiological effects of piperine. (A) Current voltage relations recorded prior and after application of 10 µM piperine to rNa_v1.4. Data from multiple paired experiments are included in the figure. Note the negative shift in half activation potential in the presence of piperine. (B) Steady state inactivation curves for rNa_v1.4 in the absence (wt) and presence of 10 µM piperine. No significant shift was observed. (C) Ensemble dose response curve for tonic rNa_v1.4 channel inhibition by piperine. The solid line is a fit via the Hill equation (IC50 10 µM ± 4 µM). (D) Effects of 10 µM piperine on rat Ca_v1.2, human LVA calcium channels and rat Na_v1.4, (n = 4-5 per channel). Error bars reflect standard errors. The asterisk denotes that rNa_v1.4 block was statistically greater relative to the other channels (*p < 0.05).

Table 5. Biophysical parameters of rNav1.4 sodium channels in the absence and the presence of piperine

	Va (mV)	Vh (mV)
rNav1.4 wt	−26.0	−63.3
10 µM Pip	−34.0	−66.2

Significant as compared to wt * p<0.05