Abstracts

Efficacy of triple-drug therapy of stiripentol, clobazam and sodium valproate in a hyperthermia-induced seizure mouse model of Dravet Syndrome

Abstract number : 887
Submission category : 2. Translational Research / 2D. Models
Year : 2020
Submission ID : 2423221
Source : www.aesnet.org
Presentation date : 12/7/2020 1:26:24 PM
Published date : Nov 21, 2020, 02:24 AM

Authors :
Jeffrey Mensah, University of Utah; Chelsea Pernici - University of Utah; Kristina johnson - University of Utah; Lauren Buxton - University of Utah; Cameron Metcalf - University of Utah; Karen Wilcox - University of Utah;


Rationale:
Dravet syndrome (DS) is a severe early-onset intractable genetic epileptic encephalopathy accompanied by impaired psychomotor and neurologic development. DS is one of the most highly pharmaco-resistant forms of epilepsy. Despite therapy with anti-seizure drugs (ASD) used as either monotherapy or polytherapy, there is no discernable best treatment for reducing seizure frequency, to prevent the occurrence of status epilepticus, and to optimize the development of cognitive functions in DS patients. ASD testing in mouse models of DS can be a useful way to identify novel treatments. However, as with people with DS, monotherapy with traditional and investigational ASDs are not always effective in preventing hyperthermia-induced seizures in DS mice. Therefore, to determine if add-on therapy can be a practical approach for drug screening in a mouse model of Dravet, we tested a recommended, second line drug regimen that combines clobazam (CLB) and sodium valproate (VPA) with the add-on drug,  stiripentol (STP). The combined use of CLB and VPA with an add-on investigational compound may be a useful approach towards screening for novel therapies in a mouse model of refractory seizures.
Method:
Both female and male heterozygous DS (Scn1aA1783/WT) experimental mice between the ages of P49 and P77 were used. DS mice (n = 10) were concurrently pre-treated with STP (100 mg/kg; i.p) and CLB (5mg/kg; i.p) at 60 minutes prior to hyperthermia and VPA (150 mg/kg; i.p) at 15 minutes before testing. Control mice (n = 10) were treated with 0.5 % methylcellulose (i.p.) at the same times prior to testing. Investigators were blinded to treatment. .Mice were placed in a clear, plastic container after the insertion of a vaseline coated rectal temperature probe. The core body temperature was then steadily elevated (1 °C  per ~2 min)  using a heat lamp until the animal seized or core temperature reached 42.5 °C. Both the temperature at which the seizure occurred and time to seizure onset were recorded. The efficacy of the triple-drug therapy was assessed by comparing the temperature threshold with that of the control group.
Results:
The median survival temperature was significantly higher at 42.5 °C in STP-CLB-VPA treated mice when compared to that of untreated mice (39.3 °C) [p-value ** = 0.0022; Log-rank (Mantel-Cox) test]. Additionally, three mice were completely protected from seizure events by the triple-drug therapy. There was an observed trend of reduced mobility among the drug-treated group in comparison with the control group.
Conclusion:
The significant increase in temperature threshold demonstrated by STP-CLB-VPA treated mice suggests efficacy of this triple-drug therapy and thus, it supports this pharmacological treatment regimen for DS. Future experiments will evaluate additional add-on therapies, including investigational drugs, to the CLB-VPA combination
Funding:
:Funded in Part by Contract # HHSN271201600048C
Translational Research