TRPV4 Blockage Inhibits the Neurogenesis in the Adult Hippocampal Dentate Gyrus Following Pilocarpine‑Induced Status Epilepticus.

Abstract

Aberrant neurogenesis in the adult hippocampal dentate gyrus (DG) contributes to synapse remodeling during temporal lobe epilepsy (TLE). Transient receptor potential vanilloid 4 (TRPV4) is involved in the pathogenesis of TLE. Activation of TRPV4 can modulate neurogenesis in the adult hippocampal DG. The present study examined whether TRPV4 is responsible for the aberrant neurogenesis in the adult hippocampal DG during TLE. Herein, administration of a TRPV4-specific antagonist, HC-067047, attenuated the enhanced neural stem cell proliferation in the adult hippocampal DG in mice following pilocarpine‑induced status epilepticus (PISE). HC-067047 reduced the heightened hippocampal protein levels of cyclin-dependent kinase (CDK) 2, CDK6, cyclin E1, cyclin A2, and phosphorylated retinoblastoma (p-Rb) observed following PISE. Meanwhile, HC-067047 inhibited the extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) pathways that were enhanced and responsible for the increased proliferation of stem cells and higher levels of CDKs, cyclins, and p-Rb protein. HC-067047 reduced the 28-day-old BrdU⁺ cells but increased the ratio of 28-day-old BrdU⁺ cells to 1-day-old BrdU⁺ cells, indicating that TRPV4 blockage reduced the number but increased the survival rate of newborn cells following PISE. Finally, HC-067047 increased the Akt signaling that was inhibited and responsible for the decreased survival rate of newborn cells following PISE. It is concluded that TRPV4 blockage inhibits stem cell proliferation in the hippocampal DG following PISE, likely through inhibiting ERK1/2 and p38 MAPK signaling to decrease cell cycle-related protein expression, and increases newborn cell survival rate likely through increasing phosphoinositide 3 kinase-Akt signaling.