Exploring the Role of MMP9 and its Association with TGFβ Signalling in Patients with Mesial Temporal Lobe Epilepsy-Hippocampal Sclerosis

Abstract

AbstractInflammation and blood brain barrier (BBB) damage are associated with epileptogenesis in Mesial Temporal lobe epilepsy with Hippocampal sclerosis (MTLE-HS). Animal studies have predicted the role of Matrix metalloproteinase 9 (MMP9) in extracellular matrix (ECM) modulation, BBB leakage and neuro-inflammation, while Transforming growth factor beta (TGFβ) signalling in astrocytes potentiates hyper-excitability leading to seizure generation. We hypothesize whether changes in activity and expression of MMP9, and the ratio of MMP9 and its inhibitor, Tissue inhibitor of metalloproteinase 1 (TIMP1), have a role in epileptogenesis in the patients with MTLE-HS through zona occludens 1 (ZO1) modulation. We also proposed the role of astrocytic TGFβ signalling in these patients. mRNA expression of MMP9 and TIMP1 was significantly up-regulated. The ratio of MMP9 to its inhibitor TIMP1 was greater than one, suggesting activation of MMP9, further confirmed by gelatin zymography. MMP9 activity as well as immunoreactivity was higher in patients with MTLE-HS as compared to non-seizure controls, whereas the immunoreactivity of ZO1 was significantly lower in the patients. The downstream TGFβ signalling effector molecules, SMAD3 and pSMAD3 immunoreactivity were also significantly higher in MTLE-HS patients and both molecules showed co-localisation with astrocytes in the hippocampal region. Further, we showed preliminary data about interaction of MMP9 and TGFβ1 in these patients as evidenced by a co-immunoprecipitation assay. This study highlighted the MMP9 and astrocytic TGFβ signalling mediated potential mechanism of epileptogenesis in MTLE-HS patients.