Abstract
Subarachnoid hemorrhage (SAH) is an important subcategory of stroke due to its unacceptably high mortality rate as well as the severe complications it causes, such as cerebral vasospasm, neurological deficits, and cardiopulmonary abnormality. Hepatoma-derived growth factor (HDGF) is a growth factor related to normal development and is involved in liver development and regeneration. This study explored the relationship between SAH and HDGF. Sixty rats were divided into five groups (n = 12/group): (A) control group; (B) rHDGF ab only group [normal animals treated with 50 µM recombinant HDGF antibodies (rHDGF ab)]; (C) SAH group; (D) SAH + pre-rHDGF ab group (SAH animals pre-treated with 50 µM rHDGF ab into the subarachnoid space within 24 h before SAH); and (E) SAH + post-rHDGF ab group (SAH animals post-treated with 50 µM rHDGF ab into the subarachnoid space within 24 h after SAH). At 48 h after SAH, serum and cerebrospinal fluid (CSF) samples were collected to measure the levels of pro-inflammatory factors by ELISA, and rat cortex tissues were used to measure protein levels by western blot analysis. Immunofluorescence staining for Iba-1, GFAP, TUNEL, and NeuN was detected proliferation of microglia and astrocyte and apoptosis of neuron cells. Neurological outcome was assessed by ambulation and placing/stepping reflex responses. Morphology assay showed that pre-treatment and post-treatment with rHDGF ab attenuated vasospasm after SAH. SAH up-regulated the levels of TNF-α, IL-1β, and IL-6 in both the CSF and serum samples, and both pre- and post-treatment with rHDGF ab inhibited the up-regulation of these pro-inflammatory factors, except for the serum IL-6 levels. Western blot analysis demonstrated that SAH up-regulated pro-BDNF and NFκB protein levels, and both pre- and post-treatment with rHDGF ab significantly reduced the up-regulation. The result from immunofluorescence staining showed that SAH induced proliferation of microglia and astrocyte and apoptosis of neuron cells. Both pre- and post-treatment with rHDGF ab significantly attenuated proliferation of microglia and astrocyte and inhibited apoptosis of neuron cells. Furthermore, treatment with rHDGF ab significantly improved neurological outcome. Blocking HDGF attenuates neuron cell apoptosis and vasospasm through inhibiting inflammation in brain tissue at early phase after SAH.
Highlights
Brain injury that occurs at the time of bleeding is the leading cause of mortality (30–70%) following subarachnoid hemorrhage (SAH) [1, 2]
Control rat HDGF (rHDGF) ab SAH + pre-rHDGF 1.12 ± 0.64* 1.25 ± 0.71* ab SAH + post-rHDGF 1.38 ± 0.52* 1.25 ± 0.46* ab Neurological outcome was assessed by ambulation and placing/stepping reflex responses within 48 h after inducing SAH
Pre-treatment with rHDGF ab significantly decreased both the ambulation (1.12 ± 0.64; P < 0.05) and the placing/stepping reflex (1.25 ± 0.71) scores when compared with the SAH group
Summary
Brain injury that occurs at the time of bleeding is the leading cause of mortality (30–70%) following subarachnoid hemorrhage (SAH) [1, 2]. SAH survivors are at risk of developing delayed cerebral vasospasm, delayed cerebral. Delayed vasospasm develops in approximately 70% of patients between 3 and 14 days after SAH [1, 2]. It has been considered as the single and the most important cause of delayed cerebral ischemia and poor outcome [3]. Cerebral vasospasm following aneurysmal SAH is the leading cause of death and disability after aneurysm rupture [5]. Cerebral ischemia secondary to vasospasm occurs in 20 to 30% of these patients and has been correlated with a 1.5to threefold increase in mortality in the first 2 weeks after
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