Early Cerebral Blood Flow Changes, Cerebrovascular Reactivity and Cortical Spreading Depolarizations in Experimental Mild Traumatic Brain Injury Model.

AIM: To investigate the spatiotemporal dynamics of early cerebral blood flow (CBF) changes, cerebrovascular reactivity (CVR), and vascular responses to cortical spreading depolarization (CSD) in an experimental mild traumatic brain injury (mTBI) model with laser speckle contrast imaging (LSCI) technique. MATERIAL AND METHODS: The weight-drop model was used to induce blunt head trauma. The mice were divided into two groups as mild TBI (n=12), and sham (n=6). The animals underwent continuous LSCI before and for 1 hour after trauma to evaluate the regional CBF changes, CVR in response to CO2, and CSD-associated vascular responses induced by pinprick. RESULTS: Our minor blunt head trauma protocol induced CSD in only 2 (16.7%) animals, which were excluded from further analyses. Of the remaining animals, 30% showed slight hyperemia following trauma, with mild ipsilateral hemisphere oligemia (15%?20% decrease in CBF) on average compared to baseline (p=0.027) and contralateral hemisphere (p=0.029). Maximal CBF decrease was measured in the peri-impact area (24.1% ± 5.1%). No significant difference was found between the sham and mTBI groups and two hemispheres of the mTBI group or pre/post-CSD periods of CO2 reactivity, as well as the characteristics of vascular CSD responses (net ischemia: 52.3% ± 2.6% vs. 56.3% ± 1.9% and prolonged oligemia duration 44.8 ± 1.8 min vs. 49.8 ± 2.3 min). CONCLUSION: The ipsilateral hemisphere, particularly in the peri-impact area, had mild hypoperfusion, within the first hour of minor blunt head trauma in mice. Nonetheless, mTBI does not alter CVR and vascular responses to an induced CSD, thus the overall CVR is largely preserved in mTBI without significant structural damage despite a mildly decreased CBF in the hyperacute phase.

Papaverine provides neuroprotection by suppressing neuroinflammation and apoptosis in the traumatic brain injury via RAGE- NF-B pathway.

The receptor for advanced glycation end products (RAGE)- Nuclear Factor kappa B (NF-κB) signal pathway may represent a new target for the treatment of traumatic brain injury (TBI). The aim of the study is to investigate effects of papaverine on secondary signaling mechanisms through this pathway in mice TBI model.Immunohistochemically, while the number of RAGE and NF- κB positive cells, apoptotic cells increased, the number of NeuN positive cells reduced in TBI.Papaverine reduced the number of RAGE positive cells on glia and the number of NF- κB positive cells on both neuron and glia. At the same time, it decreased the number of microglia labeled with P2RY12 increased due to TBI. It also increased the NeuN positive cells and mitigated the brain edema. Results of this study showed that papaverine reduced TBI- induced neuroinflammation and apoptosis, also provided neuroprotection via the RAGE- NF-κB signal path, which is one of the possible mechanisms in TBI.

In vitro effects of phenytoin and DAPT on MDA-MB-231 breast cancer cells.

Voltage-gated sodium channel (VGSC) activity enhances cell behaviors related to metastasis, such as motility, invasion, and oncogene expression. Neonatal alternative splice form of Nav1.5 isoform is expressed in metastatic breast cancers. Furthermore, aberrant Notch signaling pathway can induce oncogenesis and may promote the progression of breast cancers. In this study, we aimed to analyze the effect of the nNav1.5 inhibitor phenytoin and Notch signal inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl ester (DAPT) on triple negative breast cancer cell line (MDA-MB-231) via inhibition of nNav1.5 VGSC activity and Notch signaling, respectively. In order to determine the individual and combined effects of these inhibitors, the 4-[3-(4-iyodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1) test, wound healing assay, and zymography were performed to detect the proliferation, lateral motility, and matrix metalloproteinase-9 (MMP9) activity, respectively. The expressions of nNav1.5, Notch4, MMP9, and tissue inhibitor of metalloproteinases-1 (TIMP1) were also detected by quantitative real-time reverse transcriptase-polymerase chain reaction. DAPT caused an antiproliferative effect when the doses were higher than 10 µM, whereas phenytoin showed no inhibitory action either alone or in combination with DAPT on the MDA-MB-231 cells. Furthermore, it was found that the lateral motility was inhibited by both inhibitors; however, this inhibitory effect was partially rescued when they were used in combination. Meanwhile, the results showed that the MMP9 activity and the ratio of MMP9 mRNA to TIMP1 mRNA were only decreased by DAPT. Thus, we conclude that the combined effect of DAPT and phenytoin is not as beneficial as using DAPT alone on MDA-MB-231 breast cancer cells.