Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model.

Increased calcium influx secondary to glutamate induced excitotoxicity initiates and potentiates devastating pathological changes following ischemic stroke. Pertussis toxin (PTx), a G-protein blocker, is known to suppress intracellular calcium accumulation. We hypothesize that PTx can protect against stroke by blocking calcium influx. In a permanent middle cerebral artery occlusion model, PTx (1000 ng) was given intraperitoneally 30 min after inducing stroke. Magnetic Resonance Imaging of perfusion and T2-weighted brain scans were obtained to evaluate cerebral blood flow (CBF) and infarct volume. Primary neuronal culture was used to test glutamate induced excitotoxicity and calcium influx. We established a non-linear exponential curve model to minimize variations in animal cerebrovasculature. A reduction of 40-60% in relative CBF was a critical window where infarct volume started to increase as rCBF reduced. PTx showed maximal effects in reducing infarct volume at this window. In vitro studies further demonstrated PTx increased neuronal cell survival by decreasing glutamate-induced calcium influx into neurons and preventing neurons from apoptosis. PTx salvages the ischemic penumbra by blocking calcium influx. This provides us a new mechanism upon which experimental therapies can be explored to treat ischemic stroke. In ischemic stroke, excessive glutamate binds to AMPA receptor that depolarizes calcium channel and/ or NMDA receptor. Both of them allow calcium to enter the cell. The overload of calcium triggers cellular cascade that includes Caspase activation and release, leading to pre-mature cell death. We have demonstrated that PTx, a G-protein inhibitor, blocks calcium entry which in turn prevents further cellular damage.

Long-term outcomes of trapping vertebral artery-posterior inferior cerebellar artery dissecting aneurysms after revascularization.

OBJECTIVE: This study is designed to evaluate the long-term outcome of trapping vertebral artery-posterior inferior cerebellar artery (VA-PICA) dissecting aneurysms after revascularization. MATERIALS AND METHODS: Five patients with VA-PICA dissecting aneurysms were treated surgically between 2007 and 2010. All the aneurysms were trapped through a far-lateral approach after revascularization of the PICAs by occipital artery-posterior inferior cerebellar artery (OA-PICA) bypass. All patients were scheduled for clinical follow-up in the out-patient department at 3 months, 6 months, then annually. Computed tomography (CT) scan and CT angiography, or magnetic resonance (MR) imaging and MR angiography were performed to assess the anastomosis and cerebral blood supply. RESULTS: Among the five patients, two of them did not have any neurological deficit after surgery, the other three had post-operative lower cranial nerve palsy but recovered completely within 6 months. Post-operative cerebral angiography (received by two patients) and CT angiography (received by the other three patients) showed patent bypasses in all patients and there was no reappearance of the aneurysms. After following-up from 47 to 74 months (61 month is the median follow-up period), all patients showed excellent outcomes. CONCLUSION: Trapping the aneurysms after revascularization of PICAs by OA-PICA bypass is a safe method to treat the VA-PICA dissecting aneurysms.

A solitary hemangioblastoma located on the trochlear nerve.

Hemangioblastomas are tumors of the central nervous system that originate from the vascular system. They are most commonly composed of stromal cells in small blood vessels and usually occur in the cerebellum and spinal cord. We report a rare instance of a patient with a solitary hemangioblastoma located on the trochlear nerve. A 27-year-old woman presented with sudden onset of headache, vomiting, and diplopia. Imaging studies revealed a round mass lesion anterior to the pons with subarachnoid hemorrhage in the basal cisterns of the posterior fossa extending to the fourth ventricle. A biopsy confirmed it was a hemangioblastoma.

Pertussis toxin attenuates experimental autoimmune encephalomyelitis by upregulating neuronal vascular endothelial growth factor.

We have reported earlier that pertussis toxin (PTx) attenuates the motor deficits in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. PTx protects neurons from inflammatory insults. Vascular endothelial growth factor (VEGF) is also neuroprotective. However, the effect of PTx on VEGF has never been studied. We investigated whether PTx modulates neuronal VEGF expression and how it affects the pathogenesis of EAE. EAE was induced by injecting myelin oligodendrocyte glycoprotein 35-55 peptides with adjuvants into C57BL/6 mice. Clinical scores of EAE were evaluated daily for 19 days. Brain and spinal cord samples were collected and assessed for inflammation and demyelination. VEGF, NeuN for neurons, and Caspase-3 for apoptosis were stained for localization using immunohistochemistry techniques, followed by western blot analysis for quantification. Primary neurons were cultured to assess the direct effect of PTx on neuronal VEGF expression. PTx treatment increases neuronal VEGF expression by up to ∼75% in vitro and ∼60% in vivo, preventing neurons from apoptosis. This leads to resolution in inflammation and remyelination and amendment in motor deficits. Our findings suggest that upregulation of endogenous neuronal VEGF by PTx protects motor deficits in EAE and it is a potential therapeutic option for multiple sclerosis.