The Traf2 and NcK interacting kinase inhibitor NCB-0846 suppresses seizure activity involving the decrease of GRIA1

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Epilepsy is a common neurological disorder characterized by recurrent seizures.
• Temporal lobe epilepsy (TLE) is a frequent medically intractable form.
• The role of Traf2-and NcK-interacting kinase (TNIK) in epilepsy is currently unclear.

Purpose of the Study:

• To investigate the expression of TNIK in epilepsy.
• To explore the therapeutic potential of the TNIK inhibitor NCB-0846 in epilepsy models.
• To elucidate the underlying molecular mechanisms of TNIK's involvement in epilepsy.

Main Methods:

• Western blotting, immunofluorescence, and immunohistochemistry were used to assess TNIK expression in TLE patients and a pilocarpine-induced rat epilepsy model.
• A pentylenetetrazole (PTZ)-induced epilepsy rat model was employed to evaluate the effects of NCB-0846.
• Coimmunoprecipitation (Co-IP)/mass spectrometry (MS) and subcellular fractionation identified TNIK interactors and assessed NCB-0846's impact on postsynaptic density (PSD) proteins.

Main Results:

• TNIK expression was significantly decreased in epilepsy model rats and TLE patients compared to controls.
• NCB-0846 treatment delayed kindling progression and reduced seizure severity in the PTZ-induced epilepsy model.
• Co-IP/MS identified 63 candidate TNIK interactors, including CaMKII. TNIK correlated with GRIA1, SYN2, PSD-95, CaMKIV, GABRG1, and GABRG2. NCB-0846 treatment decreased GRIA1 levels in hippocampal lysates and PSDs.

Conclusions:

• TNIK expression is reduced in epilepsy, suggesting its involvement in the pathology.
• The TNIK inhibitor NCB-0846 demonstrates potential as an antiepileptic agent by modulating seizure activity and progression.
• TNIK's interaction with key synaptic proteins like GRIA1 may underlie its role in epilepsy, offering a novel therapeutic target.