Infantile NCL (INCL) is a neurodegenerative autosomal recessive disease caused by a deficiency in the lysosomal enzyme palmitoyl-protein thioesterase-1 (PPT1) which catalyzes the cleavage of long-chain fatty acids (predominantly palmitate) from proteins. Patients with INCL appear unaffected at birth. However, by 1 to 1.5 years, they exhibit a constellation of symptoms including visual loss, motor impairments and death by 5-6 years of age. One of the most debilitating features of INCL is the development of intractable seizures starting between 16 and 24 months. INCL patients experience myoclonic jerks that progress to tonic-clonic seizures that can occur hundreds of times each day. Most INCL children quickly become tolerant to standard antiepileptic drugs (AEDs). Further, some AEDs (eg. carbamazepine and lamotrigine) can exacerbate the seizures. It is clear that there is an urgent need for a safe and effective treatment for INCL seizures. A murine model of PPT1-deficiency is available that shares most of the biochemical, histological and clinical/behavioral features of INCL, including severe spontaneous seizures. Cannabidiol (CBD) is one of at least 85 identified phytocannabinoids found in Cannabis sativa L which is reported to have antiepileptic, neuroprotective and anti- inflammatory effects. CBD is believed to work either directly or indirectly through the endocannabinoid receptor CB1. Unfortunately, much of the excitement surrounding the use and potency of CBD for the treatment of a wide range of seizure disorders comes from anecdotal information from case reports or uncontrolled studies using crude, poorly characterized preparations. We have a unique opportunity to determine the effectiveness of CBD at reducing seizures in an authentic model of INCL that has spontaneous seizures. We can also simultaneously determine the neuroprotective and anti-inflammatory effects of CBD. The overall goals of this proposal are to determine: 1) the effects of CBD on the seizure phenotype, neurodegeneration and neuroinflammation in the INCL mouse, 2) the role of CB1r in the development of seizures in the INCL mouse and 3) the role of CB1r in the antiepileptic effects of CBD. We will accomplish these goals with the following Specific Aims:
Aim 1 : We will determine if cannabidiol alters the seizure phenotype and has neuroprotective and anti- inflammatory effects in the mouse model of INCL.
Aim 2 : We will determine if the seizure phenotype of the INCL mouse and the effects of CBD are mediated through the endocannabinoid receptor, CB1.
Infantile Neuronal Ceroid Lipofuscinosis (INCL, Infantile Batten disease) is an invariably fatal pediatric neurodegenerative disease. One of the clinical signs that greatly decreases the quality of life for these children is the development of intractable seizures. In this proposal we will determine the effectiveness of cannabidiol (derived from the cannabis plant) to decrease or eliminate the seizures, neurodegeneration and neuroinflammation in the authentic murine model of INCL.
