Treatment with vascular endothelial growth factor-A worsens cognitive recovery in a rat model of mild traumatic brain injury

Abstract

Mild traumatic brain injury (mTBI) is a common and unmet clinical issue, with limited treatments available to improve recovery. The cerebrovascular system is vital to provide oxygen and nutrition to the brain, and a growing body of research indicates that cerebrovascular injury contributes to mTBI symptomatology. Vascular endothelial growth factor-A (VEGF-A) is a potent promoter of angiogenesis and an important modulator of vascular health. While indirect evidence suggests that increased bioavailability of VEGF-A may be beneficial after mTBI, the direct therapeutic effects of VEGF-A in this context remains unknown. This study therefore aimed to determine whether intracerebroventricular administration of recombinant VEGF-A could improve recovery from mTBI in a rat model. Male and female Sprague–Dawley rats were assigned to four groups: sham + vehicle (VEH), sham + VEGF-A, mTBI + VEH, mTBI + VEGF-A. The mTBI was induced using the lateral impact model, and treatment began at the time of the injury and continued until the end of the study. Rats underwent behavioral testing between days 1 and 10 post-injury, and were euthanized on day 11 for post-mortem analysis. In males, the mTBI + VEGF-A group had significantly worse cognitive recovery in the water maze than all other groups. In females, the VEGF treatment worsened cognitive performance in the water maze regardless of mTBI or sham injury. Analysis of hippocampal tissue found that these cognitive deficits occurred in the presence of gene expression changes related to neuroinflammation and hypoxia in both male and female rats. These findings indicate that the VEGF-A treatment paradigm tested in this study failed to improve mTBI outcomes in either male or female rats.

Treatment with the vascular endothelial growth factor-A antibody, bevacizumab, has sex-specific effects in a rat model of mild traumatic brain injury

“…The cannula (Alzet®, brain kit 2) was implanted into the lateral ventricle at the following coordinates relative to the bregma: posterior 0.2 mm, lateral 1.6 mm and at 4.5 mm depth from skull surface. 25 , 32 – 34 The cannula was stabilized to the skull using dental cement and two stainless-steel screws inserted into the skull. The cannula tubing was sealed, and the incision on the head was sutured.…”

“…Whilst still under anesthetic after the pump implantation, the rat underwent a LI-induced mTBI or a sham injury. 32 , 37 , 38 Rats were placed sternally in the device on a Teflon® board, with the left temporal lobe area positioned against the impactor. The impactor propelled a 50 g weight using pneumatic pressure at 14 m/s (∼137 G) into a helmet-like metal plate (30 × 13 × 3mm 3 ), resulting in the acceleration of the rat head and a 180° lateral rotation.…”

“…Consistent with clinical mTBI, a single LI does not result in macroscopic structural brain damage assessed via conventional neuroimaging (e.g., structural MRI); 38 however it does induce neuroinflammation, axonal injury, and behavioral deficits. 32 , 39 , 40 The rat was then removed from the device, and the rat’s self-righting reflex time and body weight was recorded ( Table 1 ). Sham-injured rats underwent the identical procedures (i.e., ICV cannulation, pump implantation, anesthesia, placed in LI chamber), except that the LI was not induced.…”

“… 30 , 31 However, a recent study from our laboratory found that immediate and continuous treatment with VEGF-A did not improve subacute recovery in either male or female rats given an mTBI, with some evidence that it was actually detrimental. 32 Therefore, the aim of the present study was to further our understanding of the role of VEGF-A in mTBI by blocking its activity with BEV in female and male rats.…”

Repetitive mild traumatic brain injury elicits a reactive microglial morphology and elevates serum neurofilament light levels, independent of NLRP3 inflammasome inhibition

“…MCC950, a CNS-penetrating and speci c NLRP3 in ammasome inhibitor [27,39], was delivered via subcutaneous mini-osmotic pump (Model 2002, Alzet, CA, USA). To implant the pump, rats were lightly anesthetised with iso urane and a small incision was made between the scapulae for the osmotic pump to be inserted subcutaneously [40]. The pump was lled following manufacturer's instructions, and dispensed MCC950/saline at a rate of 0.5 µL/hour.…”