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Biomedical subjects

Ronen R Leker

Publications and source records attributed to Ronen R Leker.

12 recordsLinked to original sources
PubMed2006

Long-lasting regeneration after ischemia in the cerebral cortex.

BACKGROUND AND PURPOSE: Because fibroblast growth factor 2 is a mitogen for central nervous system stem cells, we explored whether long-term fibroblast growth factor 2 delivery to the brain can improve functional outcome and induce cortical neurogenesis after ischemia. METHODS: Rats underwent permanent distal middle cerebral artery occlusion resulting in an ischemic injury limited to the cortex. We used an adeno-associated virus transfection system to induce long-term fibroblast growth factor 2 expression and monitored behavioral and histological changes. RESULTS: Treatment increased the number of proliferating cells and improved motor behavior. Neurogenesis continued throughout 90 days after the ischemia, and the occurrence of newly generated cells with characteristics of neural precursors and immature neurons was most evident 90 days after treatment. CONCLUSIONS: Focal cortical ischemia elicits an ongoing neurogenic response that can be enhanced with fibroblast growth factor 2 leading to improved functional outcome.

Animals↗
PubMed2006

Notch signalling regulates stem cell numbers in vitro and in vivo.

The hope of developing new transplantation therapies for degenerative diseases is limited by inefficient stem cell growth and immunological incompatibility with the host. Here we show that Notch receptor activation induces the expression of the specific target genes hairy and enhancer of split 3 (Hes3) and Sonic hedgehog (Shh) through rapid activation of cytoplasmic signals, including the serine/threonine kinase Akt, the transcription factor STAT3 and mammalian target of rapamycin, and thereby promotes the survival of neural stem cells. In both murine somatic and human embryonic stem cells, these positive signals are opposed by a control mechanism that involves the p38 mitogen-activated protein kinase. Transient administration of Notch ligands to the brain of adult rats increases the numbers of newly generated precursor cells and improves motor skills after ischaemic injury. These data indicate that stem cell expansion in vitro and in vivo, two central goals of regenerative medicine, may be achieved by Notch ligands through a pathway that is fundamental to development and cancer.

Animals↗
PubMed2006

Manipulation of endogenous neural stem cells following ischemic brain injury.

The use of cell-based therapy is a valid therapeutic approach to ischemic brain injury. Endogenous neural stem cells (NSCs) have been identified in the central nervous system where they reside largely in the subventricular zone and in the subgranular zone of the hippocampus. Endogenous NSCs are capable of self-renewal and differentiation into functional brain cells. This paper summarizes the evidence recently gathered in support of a therapeutic role for endogenous NSCs in acute experimental stroke.

Animals↗
PubMed2006

Novel therapies for acute ischemic stroke.

Acute ischemic stroke is one of the leading causes of mortality and chronic disability in the western world. Yet, despite the enormous socioeconomic burden that it imposes, therapies to combat AIS are not widely available. Moreover, revascularization of the ischemic tissue with tissue plasminogen activator, the only FDA-approved therapy for AIS, is hampered by a very narrow therapeutic time window and is only used in a minority of patients. Cerebral ischemia leads to brain damage caused by several pathologic mechanisms that can potentially be blocked by neuroprotective drugs that aim to salvage the ischemic penumbra. However, despite numerous clinical trials, no single drug candidate has proved efficacious in AIS. The current situation calls for novel therapeutic strategies to be used in acute ischemic stroke. This review surveys some of these novel and promising cutting edge therapies.

Benzenesulfonates↗
PubMed2004

The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha.

No neuroprotective compounds are clinically available for the treatment of ischemic stroke. The potential salutary effect of pifithrin alpha, a novel-specific inhibitor of the transcription factor p53, administered 1-6 h following focal reversible cerebral ischemia, was investigated. Studies measuring histological, motor, and behavioral outcomes showed significant improvements in pifithrin alpha-treated animals. Pifithrin alpha reduced the number of apoptotic cells in the ischemic brain by inhibiting the binding of p53 to its DNA sites as it reduced the expression of the p53-related gene p21(WAF) without changing the amount of p53 protein itself.

Animals↗
PubMed2004

Using endogenous neural stem cells to enhance recovery from ischemic brain injury.

The use of cell-based therapy may be a valid therapeutic approach to ischemic brain injury. Stem cells have been proposed as a new form of cell based therapy in a variety of disorders, including acute and degenerative brain diseases. Up to date most efforts have concentrated on transplantation of embryonic stem cells (ESC) or neural stem cells (NSCs) obtained from immortalized cell lines into the diseased brain. These procedures require harvesting the appropriate stem cell, expansion in vitro and transplantation. Endogenous NSCs have been identified in the central nervous system where they reside largely in the subventricular zone and in the subgranular zone of the hippocampus. Endogenous NSCs may be capable of self-renewal and differentiation into functional glia and neurons. Manipulation of endogenous NSCs may bypass the need to use ESC as a form of therapy thus avoiding the complex ethical and biological issues involved with ES cells or immortalized cell lines. This review summarizes the evidence recently gathered in support of a therapeutic role for endogenous NSCs in acute experimental stroke.

Animals↗
PubMed2003

Emergent stenting to treat patients with carotid artery dissection: clinically and radiologically directed therapeutic decision making.

BACKGROUND AND PURPOSE: Carotid artery dissection (CAD) is a common cause of stroke in young patients. Clots formed at the low-flow zone in the false arterial lumen may give rise to distal emboli, and the mural hematoma may eventually occlude the artery. Anticoagulation is currently the accepted treatment, but it is unknown which patients will improve spontaneously, which will respond to anticoagulation, and which will have an exacerbation of ischemic symptoms despite therapy. Endovascular treatment of CAD may be an attractive alternative to anticoagulation, and methods of identifying patients who stand to benefit from such therapy need to be established. METHODS: We present here 3 cases of spontaneous symptomatic CAD in which endovascular stenting procedures were performed on the basis of a paradigm aimed at identifying potentially salvageable but at-risk brain tissue by combining clinical with MRI (diffusion and perfusion) and angiographic data. RESULTS: Diffusion-perfusion MRI mismatches and/or evidence of cerebral ischemia on angiographic parenchymography were identified in all patients. They did not respond to anticoagulation, were therefore treated with endovascular stents, and had excellent outcomes. CONCLUSIONS: Endovascular stent placement may be an immediate, effective, and safe method of restoring vessel lumen integrity. It may be considered for selected patients who are clinically symptomatic despite anticoagulant treatment and in whom neuroimaging methods suggest that the neurological signs originate from a viable, hypoperfused, ischemic penumbra.

Angiography↗
PubMed2003

Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210.

BACKGROUND AND PURPOSE: Cannabinoids confer neuroprotection in several experimental paradigms, but the responsible mechanisms remain unknown. Therefore, we sought to examine whether the synthetic CB1 agonist HU-210 is capable of reducing ischemic damage and to determine the mechanisms responsible for such protection. METHODS: Sprague-Dawley rats underwent permanent middle cerebral artery occlusion (PMCAO). After dose-response and therapeutic time window-finding experiments, the rats were injected with HU-210 (45 microg/kg IV) or vehicle 1 hour after PMCAO. Physiological parameters and cerebral blood flow in the peri-infarct zone were monitored. The animals were examined with a motor disability scale, and the infarct volumes were measured 72 hours later. We also examined the effects of the selective CB1 antagonist SR-141716 and of controlled warming on the neuroprotection conferred by HU-210. RESULTS: HU-210 reduced blood pressure and heart rate but did not alter the cerebral blood flow in the infarct border zone. Motor disability and infarct volumes were significantly reduced (by up to 77%; P<0.05) in animals treated with HU-210. A single injection of HU-210 significantly lowered the body temperature compared with vehicle as measured both at 1 hour (32.3+/-1.3 degrees C versus 35+/-1.6 degrees C; P=0.0024) and at 24 hours (31.5+/-2.5 degrees C versus 37.25+/-0.3 degrees C; P=0.0031) after PMCAO. The protective effects of HU-210 were partially reversed by pretreatment with SR-141716 but were completely abolished by warming of the animals to the levels observed in controls. CONCLUSIONS: HU-210 confers robust protection against ischemic damage. This protection is mediated at least in part by binding to CB1 receptors and is also associated with the indirect protective effects of hypothermia.

Animals↗
PubMed2003

Nicaraven Chugai.

Chugai (the Japanese subsidiary of Roche) is developing nicaraven (Antevas), a water-soluble antioxidant, for the potential treatment of disorders caused by acute cerebrovascular diseases. A registration application was filed in April 1995, and in April 2002, nicaraven was still awaiting registration in Japan. By August 2002, Chugai had filed an NDA in Japan for the additional indication of subarachnoidal bleeding.

Animals↗
PubMed2002

Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities.

Cerebral ischemia leads to brain damage caused by pathogenetic mechanisms that are also activated by neurotrauma. These mechanisms include among others excitotoxicity, over production of free radicals, inflammation and apoptosis. Furthermore, cerebral ischemia and trauma both trigger similar auto-protective mechanisms including the production of heat shock proteins, anti-inflammatory cytokines and endogenous antioxidants. Neuroprotective therapy aims at minimizing the activation of toxic pathways and at enhancing the activity of endogenous neuroprotective mechanisms. The similarities in the damage-producing and endogenous auto-protective mechanisms may imply that neuroprotective compounds found to be active against one of these conditions may indeed be also protective in the other. This review summarizes the pathogenetic events of ischemic and traumatic brain injury and reviews the neuroprotective strategies employed thus far in each of these conditions with a special emphasize on their clinical relevance and on future directions in the field of neuronal protection.

Animals↗
PubMed2002

NAP, a femtomolar-acting peptide, protects the brain against ischemic injury by reducing apoptotic death.

BACKGROUND AND PURPOSE: We sought to determine the cerebroprotective potential of NAP, a synthetic octapeptide related to vasoactive intestinal peptide. Activity-dependent neuroprotective protein mediates some of the protective effects of vasoactive intestinal peptide. The neuroprotective NAP sequence is derived from activity-dependent neuroprotective protein. METHODS: Spontaneously hypertensive rats underwent permanent middle cerebral artery occlusion by craniotomy and electrocoagulation. After dose-response and time-course experiments, the animals were injected with NAP (3 microg/kg) or vehicle intravenously 1 hour after stroke onset. Another group of rats was injected with the D-amino acid isomer of NAP (D-NAP) and served as a negative control. Rats were examined for motor and behavioral deficits 24 hours to 30 days later, and infarct volumes were determined. The effect of NAP administration on apoptotic death was determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 stainings. RESULTS: NAP significantly reduced motor disability and infarct volumes compared with vehicle or D-NAP when tested at 24 hours after stroke onset (9.67+/-1.4% versus 17.04+/-1.18% and 19.19+/-1.9% of hemispheric volume, respectively; P<0.05). NAP given 4 but not 6 hours after permanent middle cerebral artery occlusion still conferred significant neuroprotection (infarct volume 10.9+/-3.9% of hemispheric volume; P<0.05 versus vehicle). Long-term studies demonstrated that infarct volumes and disability scores remained significantly lower after 30 days in NAP-treated animals. NAP significantly reduced the number of apoptotic cells. CONCLUSIONS: Our results indicate that the durable cerebroprotection by NAP involves antiapoptotic mechanisms.

Animals↗