Dexmedetomidine post-treatment induces neuroprotection via activation of extracellular signal-regulated kinase in rats with subarachnoid haemorrhage

Abstract

Background: Dexmedetomidine, a sedative agent, provides neuroprotection when administered during or before brain ischaemia. This study was designed to determine whether dexmedetomidine post-treatment induces neuroprotection against subarachnoid haemorrhage (SAH) and the mechanisms for this effect.

Methods: Subarachnoid haemorrhage was induced by endovascular perforation to the junction of the right middle and anterior cerebral arteries in adult rats. Dexmedetomidine was applied immediately or 2 h after onset of SAH. Neurological outcome was evaluated 2 days after SAH. Right frontal cortex area 1 was harvested 24 h after SAH for western blotting.

Results: Subarachnoid haemorrhage reduced neurological scores and increased brain oedema and blood-brain barrier permeability. These effects were attenuated by dexmedetomidine post-treatment. Neuroprotection by dexmedetomidine was abolished by PD98095, an inhibitor of extracellular signal-regulated kinase (ERK) activation. Phospho-ERK, the activated form of ERK, was increased by dexmedetomidine; this activation was inhibited by PD98095.

Conclusions: Dexmedetomidine post-treatment provides neuroprotection against SAH. This effect appears to be mediated by ERK.

Keywords: dexmedetomidine; extracellular signal-regulated kinase; post-treatment; subarachnoid haemorrhage.

Fig 1

Dexmedetomidine post-treatment-induced neuroprotection. Adult male rats had SAH induced by endovascular perforation of the junction of right middle and anterior cerebral arteries. They were treated with dexmedetomidine, with the first dose given immediately or 2 h after onset of SAH. (a) representative brain images. (b) Subarachnoid haemorrhage grades. (c) Neurological scores at 24 h after onset of SAH. (b) Neurological scores at 48 h after onset of SAH. Inside boxes: 25–75% interval, including the median; n=18 for the first four groups and n=16 for the last two groups. *P<0.05 compared with sham-operated animals. ^P<0.05 compared with SAH-only group. Dex, dexmedetomidine; SAH, subarachnoid haemorrhage.

Fig 2

Dexmedetomidine post-treatment-induced reduction of brain oedema after SAH. Adult male rats had SAH induced by endovascular perforation of the junction of right middle and anterior cerebral arteries. They were treated with dexmedetomidine, with the first dose given immediately or 2 h after onset of SAH. (a) Water content in left cerebral hemisphere. (b) Water content in right cerebral hemisphere. (c) Water content in cerebellum. (d) Water content in brainstem. Results are mean (sd); n=8. *P<0.05 compared with sham-operated animals. ^P<0.05 compared with SAH-only group. Dex, dexmedetomidine; SAH, subarachnoid haemorrhage.

Fig 3

Dexmedetomidine post-treatment-induced reduction of blood–brain barrier permeability after SAH. Adult male rats had SAH induced by endovascular perforation of the junction of right middle and anterior cerebral arteries. They were treated with dexmedetomidine, with the first dose given immediately or 2 h after the onset of SAH. (a) Evans blue content in left cerebral hemisphere. (b) Evans blue content in right cerebral hemisphere. (c) Evans blue content in cerebellum. (d) Evans blue content in brainstem. Results are mean (sd); n=10 for the first four groups and n=8 for the last two groups. *P<0.05 compared with sham-operated animals. ^P<0.05 compared with SAH-only group. Dex, dexmedetomidine; SAH, subarachnoid haemorrhage.

Fig 4

Dexmedetomidine post-treatment-induced activation of ERK and neuroprotection after SAH. Adult male rats had SAH induced by endovascular perforation of the junction of right middle and anterior cerebral arteries. They were treated with dexmedetomidine, with the first dose given immediately after the onset of SAH. (a) Phospho-ERK immunoreactivity in the frontal cortex area 1. (b) Phospho-ERK immunoreactivity in the frontal cortex area 1 for animals treated with PD98095 at 30 min before dexmedetomidine application. (c) Subarachnoid haemorrhage grades. (d) Neurological scores. Results are mean (sd) [n=8 for panels (a) and (b)] or in box plot [n=16 for panels (c) and (d)]. *P<0.05 compared with sham-operated animals. ^P<0.05 compared with SAH-only group. #P<0.05 compared with SAH+dexmedetomidine group. Dex, dexmedetomidine; ERK, extracellular signal-regulated kinase; PD, PD98095; SAH, subarachnoid haemorrhage; Sal, saline.

Fig 5

Attenuation of dexmedetomidine post-treatment effects on brain oedema after SAH by extracellular signal-regulated kinase inhibition. Adult male rats had SAH induced by endovascular perforation of the junction of right middle and anterior cerebral arteries. They were treated with dexmedetomidine, with the first dose given immediately after onset of SAH. PD98095 was given 30 min before dexmedetomidine application. (a) Water content in left cerebral hemisphere. (b) Water content in right cerebral hemisphere. (c) Water content in cerebellum. (d) Water content in brainstem. Results are mean (sd); n=8. *P<0.05 compared with sham-operated animals. ^P<0.05 compared with SAH-only group. #P<0.05 compared with SAH+dexmedetomidine group. Dex, dexmedetomidine; PD, PD98095; SAH, subarachnoid haemorrhage.

Fig 6

Attenuation of dexmedetomidine post-treatment effects on blood–brain barrier permeability after SAH by extracellular signal-regulated kinase inhibition. Adult male rats had SAH induced by endovascular perforation of the junction of right middle and anterior cerebral arteries. They were treated with dexmedetomidine, with the first dose given immediately after the onset of SAH. PD98095 was given 30 min before dexmedetomidine application. (a) Evans blue content in left cerebral hemisphere. (b) Evans blue content in right cerebral hemisphere. (c) Evans blue content in cerebellum. (d) Evans blue content in brainstem. Results are mean (sd); n=8. *P<0.05 compared with sham-operated animals. ^P<0.05 compared with SAH-only group. Dex, dexmedetomidine; SAH, subarachnoid haemorrhage.