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Biomedical subjects

Julian Cahill

Publications and source records attributed to Julian Cahill.

7 recordsLinked to original sources
PubMed2006

Cathepsin and calpain inhibitor E64d attenuates matrix metalloproteinase-9 activity after focal cerebral ischemia in rats.

BACKGROUND AND PURPOSE: Matrix metalloproteinases (MMPs) and cysteine proteases (calpain and cathepsin B) play an important role in cell death and are upregulated after focal cerebral ischemia. Because there is a significant interaction between MMP-9 with calpain and cathepsin B, we investigated the role of E64d (a calpain and cathepsin B inhibitor) on MMP-9 activation in the rat focal ischemia model. METHODS: Male Sprague-Dawley rats were subjected to 2 hours of middle cerebral artery occlusion by using the suture insertion method followed by 22 hours of reperfusion. In the treatment group, a single dose of E64d (5 mg/kg IP) was administrated 30 minutes before the induction of focal ischemia, whereas the nontreatment group received dimethyl sulfoxide only. The neurological deficits, infarct volumes, Evans blue extravasation, brain edema, and MMP-9 activation in the brain were determined. RESULTS: Pretreatment with E64d produced a significant reduction in the cerebral infarction volume (353.1+/-19.8 versus 210.3+/-23.7 mm3) and the neurological deficits. Immunofluorescence studies showed MMP-9, calpain, and cathepsin B activation colocalized to both neurons and the neurovascular endothelial cells after ischemia, which was reduced by E64d. CONCLUSIONS: These results suggest that E64d treatment provides a neuroprotective effect to rats after transient focal cerebral ischemia by inhibiting the upregulation of MMP-9.

Animals↗
PubMed2006

Vasospasm and p53-induced apoptosis in an experimental model of subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Despite intensive research efforts, the etiology of vasospasm (sustained constriction of the cerebral vessels) remains unknown. In this study, we investigated the role of p53-induced apoptosis in the vasculature at 24 and 72 hours. To completely examine the apoptotic cascades, key proteins of the caspase-dependent, -independent and mitochondrial pathways were examined. METHODS: In this study, adult rats were divided into 3 groups: sham (n=21), nontreatment (subarachnoid hemorrhage [SAH]+dimethyl sulfoxide; n=42), and treatment (SAH+pifithrin-alpha) (n=42) groups. Each animal in the SAH group underwent a surgical procedure to induce SAH, and the basilar artery was harvested at 24 and 72 hours for analysis. RESULTS: We found severe vasospasm at the 24-hour time point, which persisted to 72 hours. Furthermore, we found that the markers of the apoptotic cascades rose significantly at the 24-hour time point but had dissipated by 72 hours. However, the neurological outcome and mortality scores improved at the 72-hour time point. CONCLUSIONS: Apoptosis, and in particular p53, may play an important role in the etiology of vasospasm with relation to SAH, and in this model, vasospasm persisted to 72 hours, despite the fact that apoptosis does not.

Animals↗
PubMed2006

Oxygen treatment after experimental hypoxia-ischemia in neonatal rats alters the expression of HIF-1alpha and its downstream target genes.

Recently, mounting evidence has emerged to suggest that hyperbaric oxygenation (HBOT)-induced neuroprotection after experimental global ischemia and subarachnoid hemorrhage entails a decrease in the expression of hypoxia-inducible factor-1alpha (HIF-1alpha). Therefore, the purpose of this study was to test the hypothesis that oxygen-induced neuroprotection after neonatal hypoxia-ischemia involves alterations in the expression of HIF-1alpha. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 2 h of hypoxia (8% O(2) at 37 degrees C). Pups were then treated with HBOT (2.5 ATA) or normobaric oxygenation treatment (NBOT) for 2 h. The expression and phosphorylation status of HIF-1alpha was evaluated at intervals up to 24 h after the insult, as was the expression of glucose transporter (GLUT)-1, GLUT-3, lactate dehydrogenase (LDH), aldolase (Ald), and p53. The protein-protein interaction of HIF-1alpha and p53 was also examined. An elevated expression of HIF-1alpha, GLUT-1, GLUT-3, Ald, and LDH was observed after the insult. An increase in the dephosphorylated form of HIF-1alpha was followed by an increase in the association of HIF-1alpha with p53 and an increase in p53 levels. Both HBOT and NBOT reduced the elevated expression of HIF-1alpha and decreased its dephosphorylated form. Furthermore, both treatments promoted a transient increase in the expression of GLUT-1, GLUT-3, LDH, and Ald, while decreasing the HIF-1alpha-p53 interaction and decreasing the expression of p53. Therefore, the alteration of the HIF-1alpha phenotype by a single oxygen treatment may be one of the underlying mechanisms for the observed oxygen-induced neuroprotection seen when oxygen is administered after a neonatal hypoxic-ischemic insult.

Adaptation, Physiological↗
PubMed2006

A novel neuroprotectant granulocyte-colony stimulating factor.

BACKGROUND AND PURPOSE: Granulocyte-colony stimulating factor (G-CSF) is a growth factor that orchestrates the proliferation, differentiation, and survival of hematopoietic progenitor cells. It has been used for many years in clinical practice to accelerate the recovery of patients from neutropenia after cytotoxic therapy. However, there is a growing body of evidence from experimental studies suggesting that G-CSF also has important nonhematopoietic functions in the central nervous system. SUMMARY OF REVIEW: The presence of the G-CSF/G-CSF-receptor system in the brain and its role in neuroprotection and neural tissue repair has been investigated in many recent studies. The neuroprotective actions of G-CSF have mainly been attributed to its anti-inflammatory and antiapoptotic effects. Furthermore, it induces neurogenesis and angiogenesis and improves functional recovery. In this review, we summarize the role of G-CSF and the corresponding signal transduction pathways regulated by G-CSF in neuroprotection. CONCLUSIONS: Much additional work is needed to better understand the precise mechanisms of G-CSF-induced neuroprotection. However, there is emerging data suggesting that G-CSF is a potential new agent for neuroprotection.

Animals↗
PubMed2006

Mechanisms of early brain injury after subarachnoid hemorrhage.

Apoptosis is the term given to programmed cell death, which has been widely connected to a number of intracranial pathologies including stroke, Alzheimer's disease, and more recently subarachnoid hemorrhage (SAH). Subarachnoid hemorrhage is a disease, without any form of effective treatment, that affects mainly the young and middle aged and as a result is responsible for severe disability in otherwise healthy and productive individuals. Despite intense research efforts in the field, we currently possess a very limited understanding of the underlying mechanisms that result in injury after SAH. However, a number of studies have recently indicated that apoptosis may be a major player in the pathogenesis of secondary brain injury after SAH. As a result, the apoptotic cascades present a number of potential therapeutic opportunities that may ameliorate secondary brain injury after SAH. Experimental data suggest that these cascades occur very early after the initial insult and may be related directly to physiologic sequela commonly associated with SAH. It is imperative, therefore, to obtain a thorough understanding of the early events that occur after SAH, which will enable future therapies to be developed.

Animals↗
PubMed2006

Limited role of inducible nitric oxide synthase in blood-brain barrier function after experimental subarachnoid hemorrhage.

Excessive nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) may play a pivotal role in blood-brain barrier (BBB) breakdown following subarachnoid hemorrhage (SAH). We investigated if the inhibition of iNOS could reduce BBB breakdown and cerebral edema, thereby leading to improved outcome 24 h after SAH. Forty male rats were assigned to three groups: control, SAH, and treatment groups. SAH was induced by perforating the bifurcation of the internal carotid artery. The neurological score and the mortality were evaluated 24 h after the surgery. The expression of iNOS, the concentration of NO metabolites, morphological changes in neuronal cells, water content, and IgG leakage were also evaluated. The expression of iNOS, as well as the concentration of NO metabolites, was elevated after SAH. Treatment with p-Toluenesulfonate decreased both the expression of iNOS and the concentration of NO metabolites. However, there was no significant change in water content, BBB disruption, or morphological findings between the SAH group and the treatment group. Furthermore no significant differences in neurological score or mortality were observed. The iNOS inhibitor failed to reduce BBB breakdown, brain edema, and neuronal cell death and failed to improve the neurological score and the mortality 24 h after SAH.

Animals↗