Research Interests: My research interest includes the study of cerebrovascular disease and brain trauma and involves both basic science and clinical aspects. I am particularly interested in finding novel approaches to improve outcome following ischemic and traumatic brain injury (TBI). Basic research:Earlier research projects at my laboratory looked at pharmacological and physical methods of protecting the brain against ischemic and traumatic injury. My laboratory uses multiple in-vitro and in-vivo models to study cerebral ischemia and hemorrhage. Using the PMCAO model in rats we explored whether several candidate compounds including dexanabinol, a cannabinoid like NMDA antagonist, tempol an antioxidant and NAP a novel VIP related peptide are protective after stroke.  Our results show that all of the above compounds significantly reduce brain damage after ischemic injury despite of working via different mechanisms. We further studied chemical hypothermia induced by the synthetic cannabinoid HU-210 as a neuroprotective strategy. We found that motor disability and infarct volumes were significantly reduced in treated rats. We further established that the protective effects were mediated via CB1 receptors as they were partially blocked with the antagonist SR-141716 providing evidence that chemical cooling may be easily induced and could potentially replace physical cooling in future experiments.   More recently, our research focus changed to application of cell based strategies and in particular manipulations of endogenous neural stem cells (eNSC) as a novel therapy for stroke and TBI. In this regard, I am mainly interested in the effects of growth and trophic factors on eNSC proliferation, migration and differentiation following different forms of brain injury and how this effects recovery. In one study we used in-vivo transfection with an adeno-associated viral vector to induce production of FGF2 in the rodent post ischemic brain. Our results clearly show that this strategy resulted in better functional outcome and is associated with a dramatic increase in the number of neural progenitors and newborn neurons in the peri-infarct area.  In a separate study we explored an alternative method of increasing eNSC survival after stroke by stimulation of the notch receptor with ligands such as delta-4. Our results show that stimulation resulted in greater survival of NSC with preserved differentiation capacity into newborn neurons and glia. The pathways implicated in increased survival include PI3 kinase and phosphorylation of AKT and STAT3. In a separate series of studies, we showed that stimulation of bone marrow derived cells with a combination of stem cell factor and granulocyte colony stimulating factor results in increased entry of these cells into the brain and a significant increase in angiogenesis. When we stimulated eNSC with transforming growth factor alpha delivered directly into the brain's parenchyma we observed a small but significant increase in neurogenesis accompanied by an increase in angiogenesis. Further studies in our lab also showed that stimulation of the local eNSC pool with exogenous leptin, synthetic cannabinoids, VEGF, platelet microparticles and even whole platelet lystae result in robust increments in the stem cell proliferation and migration although only a limited number of these cells went on to differentiate into neurons. Furthermore, we found that induction of neurogenesis is also accompanied by induction of angiogenesis which further contributes to the survival of neural stem cells and also to that of injured neurons. Taken together, these results indicate that several pathways can be perturbed in order to induce an increase in endogenous neurogenesis and angiogenesis that may be related to increased survival, proliferation and neuronal differentiation of these cells as well as to better survival and function of injured neurons and that these changes may be related to the better functional outcome seen in treated animals. In the very near future we plan to make the first strides towards implementing these results in the clinical realm as we look at pathways to enable translation of our results to human studies. My group currently collaborates with several on-campus groups including Prof. David Varon (in vitro and in-vivo assessment of manipulating angiogenesis and neurogenesis following ischemia using platelets and platelet microparticles), Prof. Elliott Beery (exploring the effects of leptin on neuroprotection and regeneration), Prof. Esther Shohami and Prof. Raphi Mechuolam on the use of cannabinoids for the induction of neurogenesis and angiogenesis in the brain and on the neurogenic response to traumatic brain injury.. We also collaborate with off campus groups in Israel including Prof. Avraham Zangen's group at the NegevUniversity (post ischemic brain stimulation for induction of neurogenesis). Clinical Studies: My clinical studies focus on pathophysiology, outcome parameters and novel therapies for stroke. In this capacity we established the comprehensive stroke center at Hadassah which I direct. Our center was the first to administer the thrombolytic drug tPA to stroke victims and in collaboration with Prof. Jose Cohen from the department of neurosurgery, we were the first to perform endovascular interventions in stroke patients and to date our center performs the largest numbers of endovascular reperfusion procedures in Israel. This fruitful collaboration resulted in many publications in the top tier journals of stroke. In a report published in Neurosurgery, we described our success rates in patients with basilar artery thrombosis and in a second published in Stroke we described good outcome in patients with anterior circulation stroke. These were followed by papers published in Stroke comparing tPA to endovascular treatment. Taken together these papers add to the growing body of evidence that attest to the efficacy of the endovascular approach in severe stroke and suggest that more neurologists should be involved in such therapies. Other clinical studies from our group focus on the effects of prior drug therapy on outcome after stroke. In prospective studies published in Stroke and in European Journal of Neurology we have found in two separate databases (one National and one at our center) that the use of statins prior to intracerebral hemorrhage reduces disability and results in better outcome suggesting that these drugs may have protective effects in ICH. In another study we found that patients that received thrombolysis improve faster and to larger extents when compared with patients that had similar initial stroke severity but were not given thrombolytics due to contra-indications. This paper is important in showing that the benefits of tPA extend into the rehabilitation period. More recently, we aim to show that diffusion weighted imaging (DWI) MRI is the best screening test for stroke patients arriving at the ER and we have already published our initial results showing that DWI can differ stroke from stroke mimics. Ultimately, we believe that in order to achieve better results in stroke victims it would be necessary to combine accurate stroke diagnosis (e.g. DWI MRI), revascularization techniques (e.g. tPA, endovascular treatment etc), neuroprotective strategies (e.g. hypothermia) and cell therapy (e.g. manipulation of endogenous neural stem cells to improve function of surviving neurons and possibly replacing dead neurons). Our goal is to establish a platform for translational research to achieve these goals.