Biomedical subjects

Jeffrey J Legos

Publications and source records attributed to Jeffrey J Legos.

8 recordsLinked to original sources

PubMed2003

Caspase 3 activation is essential for neuroprotection in preconditioning.

Sublethal insults can induce tolerance to subsequent stressors in neurons. As cell death activators such as ROS generation and decreased ATP can initiate tolerance, we tested whether other cellular elements normally associated with neuronal injury could add to this process. In an in vivo model of ischemic tolerance, we were surprised to observe widespread caspase 3 cleavage, without cell death, in preconditioned tissue. To dissect the preconditioning pathways activating caspases, and the mechanisms by which these proteases are held in check, we developed an in vitro model of excitotoxic tolerance. In this model, antioxidants and caspase inhibitors blocked ischemia-induced protection against N-methyl-d-aspartate toxicity. Moreover, agents that blocked preconditioning also attenuated induction of HSP 70; transient overexpression of a constitutive form of this protein prevented HSP 70 up-regulation and blocked tolerance. We outline a neuroprotective pathway where events normally associated with apoptotic cell death are critical for cell survival.

Animals↗

PubMed2003

Update on pharmacological strategies for stroke: prevention, acute intervention and regeneration.

Given the few options that are currently available for patients following ischemic stroke, the search for novel therapeutic approaches becomes more critical. Pharmaceutical intervention strategies for the treatment of stroke include preventative (prophylactic or stroke pretreatment), neuroprotective (early acute post-stroke treatment) and regenerative (delayed post-stroke treatment for long-term benefit) therapeutic approaches. Experimental evidence has suggested that the majority of stroke patients have a slow evolution of brain injury that occurs over several hours. This 'evolving stroke' may ultimately be a realistic target for therapeutic intervention, with the goal of inhibiting the progression of detrimental changes that normally follow the acute ischemic event. Preventing or reducing this delayed cellular injury may improve neurological outcome and also facilitate brain recovery from injury. Significant impact on stroke can be expected as additional research is conducted on biological targets or processes important in facilitating the brain's regenerative capacity following cellular/tissue loss. This review provides updates on stroke prevention therapies (anticoagulant and antiplatelet), the advances in the development of pharmacological agents that target the acute phase of stroke (thrombolytics and neuroprotective drugs), and newly evolving approaches that may facilitate brain regeneration (i.e., neurobehavioral recovery) following brain damage.

Animals↗

PubMed2002

The selective p38 inhibitor SB-239063 protects primary neurons from mild to moderate excitotoxic injury.

Inhibition of the p38 mitogen-activated protein kinase (MAP Kinase) pathway reduces acute ischemic injury in vivo, suggesting a direct role for this signaling pathway in a number of neurodegenerative processes. The present study was designed to evaluate further the role of p38 MAP Kinase in acute excitotoxic neuronal injury using the selective p38 inhibitor SB-239063 (trans-1-(4hydroxycyclohexyl)-4-(fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl) imidazole). Unlike the widely used p38 inhibitor, SB-203580 (4-(4-Fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole), this second generation p38 inhibitor more selectively inhibits p38 MAP Kinase without affecting the activity of other MAP Kinase signaling pathways and provides a more accurate means to selectively assess the role of p38 in excitotoxicity that has not been previously possible. SB-239063 provided substantial protection against cell death induced by either oxygen glucose deprivation (OGD) or magnesium deprivation in cultured neurons. The ability of this compound to block excitotoxicity was not due to direct inhibition of N-methyl-D-aspartate (NMDA) receptor-mediated currents as SB-239063 did not alter NMDA electrophysiological responses. SB-239063 did not protect against a severe excitotoxic insult induced by 60-min exposure to NMDA. However, when tested against a less severe, brief (5 min) NMDA exposure, p38 inhibition provided substantial protection. These data demonstrate that inhibition of p38 MAP Kinase can confer neuroprotection in vitro against mild but not severe excitotoxic exposure, and suggests that other additional pathways/mechanism(s) may be involved in severe excitotoxic cell death.

Animals↗

PubMed2002

Programmable microchip monitoring of post-stroke pyrexia: effects of aspirin and paracetamol on temperature and infarct size in the rat.

BACKGROUND: Recent studies have demonstrated spontaneous and prolonged hyperthermia following stroke in both humans and rodents. However, a full characterization of these pyretic changes and the effects of anti-pyretic drugs on outcome is not available. METHODS: The aims of this study were to monitor conscious body temperature (n=10 per group) using programmable microchips for up to 24 h in rats following either permanent (p) or 90 min transient (t) middle cerebral artery occlusion (MCAO) or sham surgery, and to evaluate the relationship to hypothalamic damage. Also, the effects of anti-pyretic drug therapy on body temperature and infarct volume were evaluated in animals treated with vehicle, optimal doses of either aspirin or paracetamol (250 mg/kg i.p.) following pMCAO (n=10 per group). RESULTS: At 1 h, body temperature significantly (P<0.01) increased to 38.6+/-0.2 degrees C following tMCAO and 38.9+/-0.1 degrees C following pMCAO compared with sham-operated animals (37.1+/-0.1 degrees C). Sustained hyperthermia (> or =38.1 degrees C) was observed for up to 24 h following pMCAO but approached baseline within 30 min (37.6+/-0.2 degrees C) following tMCAO with reperfusion. The post-stroke pyrexia was related to the degree of ischemia where hypothalamic damage was observed in (80%) of the animals undergoing pMCAO and (0%) in the tMCAO group (P<0.05). Treatment with paracetamol (250 mg/kg i.p.) significantly attenuated (P<0.05) but did not normalize core body temperature up to 2 h (38.2+/-0.4 degrees C) compared with vehicle treated animals (39.3+/-0.1 degrees C). Aspirin had no effect on temperature under these conditions. Hypothalamic damage and lesion volume were not different between animals treated with paracetamol (253.3+/-8.5 mm(3)), aspirin (264.0+/-11.6 mm(3)) or vehicle (274.4+/-8.2 mm(3)). CONCLUSIONS: This study is the first to demonstrate the utility of programmable microchips to monitor serial changes in post-stroke hyperthermia. The sustained post-stroke pyrexia and negative effects of antipyretic treatment may be attributed to the extensive hypothalamic injury suggesting that better pharmacologic approaches to reduce body temperature should be identified and evaluated for brain protection in severe experimental stroke.

Acetaminophen↗

PubMed2002

LEX032, a novel recombinant serpin, protects the brain after transient focal ischemia.

This investigation examined the effectiveness of a serine protease inhibitor (LEX032) when used as a cerebral protective agent after ischemia. Focal cerebral ischemia in the rat was produced by intravascular occlusion of the middle cerebral artery for a period of 30 min. Just prior to thread withdrawal (i.e., reperfusion), rats received an iv bolus administration of either vehicle or LEX032 (50 mg/kg), an optimal dose chosen based on previous studies. Somatosensory evoked potentials (SSEP's) were monitored prior to, during, and for a period of 60 min after removal of occlusion. The animals were allowed to recover for 24 h after the ischemic insult. Cortical activity in the occluded region, as assessed by SSEPs, returned much sooner in the LEX032-treated animals (10 +/- 6 min) than in the untreated animals (40 +/- 25 min). On a scale ranging from 0 to 3, with three indicating the most severely injured, the LEX032 animals had a significantly better neurologic score (1.0 +/- 0.9) than the untreated animals (2.3 +/- 0.5) 24 h after ischemia. The improved neurobehavior was related to a 55% reduction in brain injury as assessed by TTC staining. LEX032-treated animals had significantly (P < 0.01) smaller infarcts (115 +/- 40 mm3) compared to vehicle-treated animals (263 +/- 13 mm3). In a separate group of animals (n = 6/group), leukocyte infiltration, as evaluated by tissue myeloperoxidase activity (MPO U/g tissue wt), was also significantly (P < 0.05) lower in the LEX032-treated animals (1.4 +/- 0.3) compared to vehicle-treated animals (3.6 +/- 0.7). This data demonstrates that LEX032 reduces brain injury and suggests that serine protease inhibitors may reduce ischemia/reperfusion injury by decreasing leukocyte activation and migration.

Animals↗

PubMed2002

Nonpeptide tachykinin receptor antagonists. III. SB 235375, a low central nervous system-penetrant, potent and selective neurokinin-3 receptor antagonist, inhibits citric acid-induced cough and airways hyper-reactivity in guinea pigs.

In this report the in vitro and in vivo pharmacological and pharmacokinetic profile of (-)-(S)-N-(alpha-ethylbenzyl)-3-(carboxymethoxy)-2-phenylquinoline-4-carboxamide (SB 235375), a low central nervous system (CNS)-penetrant, human neurokinin-3 (NK-3) receptor (hNK-3R) antagonist, is described. SB 235375 inhibited (125)I-[MePhe(7)]-neurokinin B (NKB) binding to membranes of Chinese hamster ovary (CHO) cells expressing the hNK-3R (CHO-hNK-3R) with a K(i) = 2.2 nM and antagonized competitively NKB-induced Ca(2+) mobilization in human embryonic kidney (HEK) 293 cells expressing the hNK-3R (HEK 293-hNK-3R) with a K(b) = 12 nM. SB 235375 antagonized senktide (NK-3R)-induced contractions in rabbit isolated iris sphincter (pA(2) = 8.1) and guinea pig ileal circular smooth muscles (pA(2) = 8.3). SB 235375 was selective for the hNK-3R compared with hNK-1 (K(i) > 100,000 nM) and hNK-2 receptors (K(i) = 209 nM), and was without effect, at 1 microM, in 68 other receptor, enzyme, and ion channel assays. Intravenous SB 235375 produced a dose-related inhibition of miosis induced by i.v. senktide in the rabbit (ED(50) of 0.56 mg/kg). Intraperitoneal SB 235375 (10-30 mg/kg) inhibited citric acid-induced cough and airways hyper-reactivity in guinea pigs. In mice oral SB 235375 (3-30 mg/kg) was without significant effect on the behavioral responses induced by intracerebral ventricular administration of senktide. Pharmacokinetic evaluation in the mouse and rat revealed that oral SB 235375 was well absorbed systemically but did not effectively cross the blood-brain barrier. The preclinical profile of SB 235375, encompassing high affinity, selectivity, oral activity, and low CNS penetration, suggests that it is an appropriate tool compound to define the pathophysiological roles of the NK-3Rs in the peripheral nervous system.

Acetates↗

PubMed2002

Non-surgical management of spinal cord injury.

Spinal cord injury remains a devastating neurological condition with limited therapeutic opportunities. Since decompressive surgery and high-dose methylprednisolone have limited utility for most patients, spinal cord injury clearly represents a major medical challenge. Experimental evidence has suggested that secondary cellular injury processes may be a realistic target for therapeutic intervention with the goal of inhibiting the progression of detrimental changes that normally follows traumatic injury to the cord. Preventing or reducing this delayed cellular injury may alone improve neurological recovery or facilitate future regenerative approaches to the injured cord. This review summarises recent advances in the development of pharmacological agents targeting the acute phase of spinal cord injury as well as potential strategies to facilitate regeneration of the spinal cord.

Clinical Trials as Topic↗

PubMed2002

Pharmacological interventions for stroke: failures and future.

Given the few options currently available for patients following ischaemic stroke, the recent disappointing failures of several large-scale Phase III clinical trials has made the search for novel therapeutic approaches even more critical. Experimental evidence has suggested that the majority of stroke patients have a slow evolution of brain injury which can occur over several hours. Progressive microcirculatory failure following the initial onset of ischaemia may contribute to the expansion of brain injury. Included among the pathophysiological changes that are speculated to occur as a secondary response to the initial ischaemia are free radical production, excitotoxicity (for example, glutamate) disruption of ionic homeostasis (for example, sodium and calcium influx), enzymatic changes, stimulation of the inflammatory process, endothelin release, activation of platelets and leukocytes, delayed coagulation and endothelial dysfunction. All of these pathophysiological reactions could contribute to an increase in local vascular resistance and therefore cause progressive hypoperfusion of the brain following the onset of stroke. The scope of this review will focus on recent clinical failures in addition to agents currently in clinical development, comparing vascular targets to the common neuroprotective strategies.

Brain↗