Epilepsy is the most prevalent neurological diseases after migraines. Current antiepileptic drug treatmentsmainly attempt to reduce excitation or enhance inhibition in order to control seizures. Unfortunately, suchtherapeutics result in a number of undesirable side-effects, and demonstrate limited efficacy against drug-resistant cases of epilepsy. So far, no treatment has been developed as an anti-epileptogenic agent, in partbecause of the limited understanding of the processes involved in the development of epilepsy. It is generallyaccepted that up to 50% of all epileptic patients become epileptic as a result of a triggering initial injury such asstatus epilepticus, stroke or traumatic brain injury. This initial triggering injury has been postulated to activate acascade of events leading to further seizures, increased brain damage and self-propagation. Calpains are afamily of soluble calcium-dependent proteases, which have been implicated in epilepsy, since they are activatedby seizures and participate in neuronal damage. Recent studies have also indicated that during earlyepileptogenesis, seizure occurrence, calpain activity and neuronal damage are correlated, and that treatmentwith a non-selective calpain inhibitor reduces the development of spontaneous recurrent seizures (SRS) in thepilocarpine model of epilepsy in rats. Our laboratory has demonstrated that calpain-1 and calpain-2, two of themajor calpain isoforms in the brain, have opposite functions in the brain. We have also found that calpain-2conditional knock-out mice with calpain-2 deletion in excitatory neurons from the forebrain show normal seizureactivity following injections of repeated low doses of kainic acid (KA) but exhibit no brain inflammation,degeneration and cognitive impairment in hippocampus-dependent learning 7 days after seizures. Similarprotective results were obtained when wild-type mice were treated daily and for seven days after seizures witha selective calpain-2 inhibitor. These results strongly support the hypothesis that calpain-2 might represent apotential therapeutic target to prevent various pathological consequences of seizures. This Phase I STTR isdirected at first determining whether a selective calpain-2 inhibitor, NA-184, might prevent the appearance ofSRSs or reduce their frequency in two mouse models of epilepsy, the repeated low doses of kainic acid (KA) orof pilocarpine models (Aim #1). In Aim # 2, we will test the effects of intranasal administration of NA-184 on KA-and pilocarpine-induced neuropathology, as intranasal delivery of a variety of anti-epileptic drugs is increasinglyused in the clinic. In Phase II of this STTR, we will further pursue the development of intranasal delivery of NA-184 as an anti-epileptic treatment. NeurAegis is a small biotech company focusing on the development ofselective calpain-2 inhibitors for the treatment of acute neuronal injury, including traumatic brain injury andrepeated concussions. This proposal is directed at expanding the potential applications of these calpain-2inhibitors by determining whether they could also be developed as potential therapeutic treatment for epilepsy.
Public Health Relevance Statement: Narrative
There are currently no drugs that provide neuroprotection after status epilepticus. While calpain has been
proposed to participate in the development of epilepsy as well as other neurodegenerative disorders, there are
no calpain inhibitors in the clinic. The present studies will test the hypothesis that a selective calpain-2 inhibitor
could prevent the occurrence of spontaneous recurring seizures following a seizure episode in two mouse
models of epilepsy, in addition to preventing several manifestations of neuropathology. These studies will provide
critical information to support the clinical development of a selective calpain-2 inhibitor for the treatment of
epilepsy.
Project Terms: 