Rationale:
Proper intracellular chloride concentration [Cl
-]
i is fundamental for physiological brain development and function. Accordingly, the aberrant expression of chloride importer NKCC1 and exporter KCC2 is implicated in several neurodevelopmental and neurological conditions, including drug-resistant epilepsy (e.g., Mesial Temporal Lobe Epilepsy (MTLE), focal cortical dysplasia (FCD) and Dravet syndrome), leading to a brain excitation/inhibition imbalance. Interestingly, NKCC1 inhibition has been proven to be an effective strategy to rescue drug-resistant epilepsy in preclinical and clinical studies and core symptoms of several other neurodevelopmental disorders. However, current unselective NKCC1 inhibitors induce diuretic effects by also inhibiting the kidney chloride-cotransporter NKCC2. This creates critical issues with treatment compliance and health concerns, strongly jeopardizing them from becoming viable therapy for chronic treatment. To overcome these issues, we developed a new class of selective NKCC1 inhibitors, which were effective in rescuing core brain-related symptoms in animal models of autism and Down syndrome, without showing any diuretic and toxic effects. Lead compound IAMA-6 is currently being evaluated in advanced preclinical studies toward its development into a clinical candidate. In this study, we evaluated the efficacy of the selective NKCC1 inhibitor IAMA-6 in improving seizure outcomes in a mouse model of MTLE, the most common form of focal refractory epilepsy.
Methods:
In the MTLE mouse model induced by intra-hippocampal kainic acid injection, we investigated the effect of intraperitoneal (10 mg/Kg) IAMA-6 administration by evaluating hippocampal discharge train and spike rate in EEG recordings.
Results:
We found that chronic treatment with IAMA-6 in epileptic mice reduced hippocampal discharge rate and intra-train spike rate compared to both baseline and vehicle-treated animals. Notably, IAMA-6 efficacy was retained after three days of drug washout.
Conclusions:
In conclusion, IAMA-6 is a solid lead compound advancing toward clinical studies and may represent an effective therapeutic strategy to improve MTLE. To further increase the translational value of IAMA-6, we are currently investigating its efficacy in restoring neuronal [Cl
-]
i directly in brain tissues from patients with MTLE and FCD. In addition, ongoing evaluation of IAMA-6 efficacy in Dravet syndrome will further expand the types of drug-resistant epilepsy and epileptic syndromes that may benefit from IAMA-6 treatment.
Funding: N/A