Dual Notch-1 pathway regulation mitigates glial activation and preserves myelin integrity: neuroprotective and anticonvulsant actions of pentoxifylline in PTZ kindling model.

OBJECTIVES

Epilepsy is a debilitating neurological disorder that drives progressive neurodegeneration, glial activation, and disrupted neuronal signaling. Despite available therapies, drug resistance and adverse effects underscore urgent need for novel interventions. This study investigated the neuroprotective and antiepileptic efficacy of pentoxifylline (PTX), a methylated xanthine derivative with anti-inflammatory and antioxidant properties, in comparison with carbamazepine (CBZ).

METHODS

Male Wistar rats were subjected to pentylenetetrazole-induced kindling to establish a chronic epilepsy model, followed by 14 days of PTX or CBZ treatment. Behavioural outcomes were assessed using Racine's seizure score, open field test, and Morris water maze test, while histopathological, immunohistochemical, and molecular analyses explored canonical and non-canonical Notch-1 signaling, glial activation, and myelin integrity.

KEY FINDINGS: PTX conferred robust neuroprotection, preserving cortical histoarchitecture. PTX attenuated canonical Notch-1 (Jagged-1/Notch-1/NICD-1/HES-1/HES-5) while enhancing non-canonical (F3/contactin/Deltex-1) cassettes. PTX suppressed the pro-inflammatory IL-1β, reduced glial fibrillary acidic protein and Iba-1 immuno-expression, and increased MBP levels. Functionally, these molecular and structural benefits are translated into reduced seizure severity and improvements in memory, cognition, and locomotor activity.

CONCLUSIONS

Overall, PTX demonstrates potent antiepileptic and neuroprotective properties, accompanied by integrated modulation of canonical and non-canonical Notch-1 signaling, highlighting its translational potential as an adjunctive therapy for refractory epilepsy.