Expression of nitric oxide synthase (NOS)-2 following permanent focal ischemia and the role of nitric oxide in infarct generation in male, female and NOS-2 gene-deficient mice

Loihl, Angela K.; Asensio, Valérie C.; Campbell, Iain L.; Murphy, Seán

doi:10.1016/s0006-8993(99)01388-8

Cited by 84 publications

(81 citation statements)

References 42 publications

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“…Others have reported similar findings in iNOS mutants where females, unlike males, sustain no reduction in ischemic damage relative to WT controls (Loihl et al, 1999). However, our observation that removal or inhibition of nNOS or PARP-1 signaling exacerbates ischemic damage in females was unexpected.…”

Section: Discussionsupporting

confidence: 81%

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

McCullough

Zeng

Blizzard

et al. 2005

J Cereb Blood Flow Metab

300

326

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It is well established that tissue damage and functional outcome after experimental or clinical stroke are shaped by biologic sex. We investigated the novel hypothesis that ischemic cell death from neuronally derived nitric oxide (NO) or poly-ADP ribose polymerase (PARP-1) activation is sexually dimorphic and that interruption of these molecular death pathways benefits only the male brain. Female neuronal nitric oxide synthase (nNOS) knockout (nNOSÀ/À) mice exhibited exacerbated histological injury after middle cerebral artery occlusion (MCAO) relative to wild-type (WT) females, unlike the protection observed in male nNOSÀ/À littermates. Similarly, treatment with the nNOS inhibitor (7-nitroindozole, 25 mg/kg) increased infarction in female C57Bl6 WT mice, but protected male mice. The mechanism for this sexually specific response is not mediated through changes in protein expression of endothelial NOS or inducible NOS, or differences in intraischemic cerebral blood flow. Unlike male PARP-1 knockouts (PARP1À/À), female PARP1À/À littermates sustained grossly increased ischemic damage relative to sex-matched WT mice. Treatment with a PARP inhibitor (PJ-34, 10 mg/kg) resulted in identical results. Loss of PARP-1 resulted in reversal of the neuroprotective activity by the female sex steroid, 17b estradiol. These data suggest that the previously described cell death pathways involving NO and PARP ischemic neurotoxicity may be operant solely in male brain and that the integrity of nNO/PARP-1 signaling is paradoxically protective in the female.

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Section: Discussionsupporting

confidence: 81%

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

McCullough

Zeng

Blizzard

et al. 2005

J Cereb Blood Flow Metab

300

326

View full text Add to dashboard Cite

show abstract

“…This may be due to differential utilization of molecular cell death pathways by males and females. In particular, this may be seen in neuronal isoforms of NOS and the DNA repair enzyme poly(ADP-ribose) polymerase (PARP-1) (Loihl et al 1999;McCullough et al 2005;Park et al 2004). Evidence suggests a role for PARP-1 in glutamate excitotoxicity.…”

Section: Sex Differences In Neural Injury and Neuroprotectionmentioning

confidence: 99%

Neurological implications of urea cycle disorders

Gropman

Summar

Leonard³

2007

J of Inher Metab Disea

191

152

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SummaryThe urea cycle disorders constitute a group of rare congenital disorders caused by a deficiency of the enzymes or transport proteins required to remove ammonia from the body. Via a series of biochemical steps, nitrogen, the waste product of protein metabolism, is removed from the blood and converted into urea. A consequence of these disorders is hyperammonaemia, resulting in central nervous system dysfunction with mental status changes, brain oedema, seizures, coma, and potentially death. Both acute and chronic hyperammonaemia result in alterations of neurotransmitter systems. In acute hyperammonaemia, activation of the NMDA receptor leads to excitotoxic cell death, changes in energy metabolism and alterations in protein expression of the astrocyte that affect volume regulation and contribute to oedema. Neuropathological evaluation demonstrates alterations in the astrocyte morphology. Imaging studies, in particular 1 H MRS, can reveal markers of impaired metabolism such as elevations of glutamine and reduction of myoinositol. In contrast, chronic hyperammonaemia leads to adaptive responses in the NMDA receptor and impairments in the glutamate-nitric oxide-cGMP pathway, leading to alterations in cognition and learning. Therapy of acute hyperammonaemia has relied on ammonia-lowering agents but in recent years there has been considerable interest in neuroprotective strategies. Recent studies have suggested restoration of learning abilities by pharmacological manipulation of brain cGMP with phosphodiesterase inhibitors. Thus, both strategies are intriguing areas for potential investigation in human urea cycle disorders.

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“…Digital photographs of all stained slices were taken and the unstained area of infarction was measured on the posterior surface of each coronal section using Scion Image Software. Infarct areas were calculated as described previously (Loihl et al, 1999), using an indirect method whereby overestimation of the infarct area because of the contribution of edema is avoided.…”

Section: Lesion Volumementioning

confidence: 99%

G-CSF Reduces Infarct Volume and Improves Functional Outcome after Transient Focal Cerebral Ischemia in Mice

Gibson

Bath

Murphy

2005

J Cereb Blood Flow Metab

156

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Growth factors possess neuroprotective and neurotrophic properties in vitro, but few have been extensively studied in vivo after stroke. In the present study, we investigated the potential functional benefits of granulocyte colony-stimulating factor (G-CSF) administration after focal cerebral ischemia. Male mice underwent 60-minute middle cerebral artery occlusion (MCAO) and received G-CSF (50 lg/kg, subcutaneously) or vehicle (saline) at the onset of reperfusion. Granulocyte colony-stimulating factor-treated mice killed at 48 hours after MCAO revealed a 445% reduction (Po0.05) in lesion volume. In terms of body weight recovery, and in tests of motor (grid test and rotarod) and cognitive ability (water maze), MCAO significantly worsened the outcome in vehicletreated mice as compared with shams (Po0.05). However, G-CSF treatment was beneficial as, compared with vehicle, this significantly improved weight recovery and motor ability. This effect was most apparent on the water maze where G-CSF-treated mice were indistinguishable from shams in terms of acquiring the task. These results indicate long-term beneficial effects of a single dose of G-CSF administered on reperfusion, and illustrate the need to further investigate the mechanisms of G-CSF action.

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Expression of nitric oxide synthase (NOS)-2 following permanent focal ischemia and the role of nitric oxide in infarct generation in male, female and NOS-2 gene-deficient mice

Cited by 84 publications

References 42 publications

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

Ischemic Nitric Oxide and Poly (ADP-Ribose) Polymerase-1 in Cerebral Ischemia: Male Toxicity, Female Protection

Neurological implications of urea cycle disorders

G-CSF Reduces Infarct Volume and Improves Functional Outcome after Transient Focal Cerebral Ischemia in Mice

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