Delayed Reduction of Ischemic Brain Injury and Neurological Deficits in Mice Lacking the Inducible Nitric Oxide Synthase Gene

Abstract

Inducible nitric oxide synthase (iNOS), an enzyme that produces toxic amounts of nitric oxide, is expressed in a number of brain pathologies, including cerebral ischemia. We used mice with a null mutation of the iNOS gene to study the role of iNOS in ischemic brain damage. Focal cerebral ischemia was produced by occlusion of the middle cerebral artery (MCA). In wild-type mice, iNOS mRNA expression in the post-ischemic brain begun between 24 and 48 hr peaked at 96 hr and subsided 7 d after MCA occlusion. iNOS mRNA induction was associated with expression of iNOS protein and enzymatic activity. In contrast, mice lacking the iNOS gene did not express iNOS message or protein after MCA occlusion. The infarct and the motor deficits produced by MCA occlusion were smaller in iNOS knockouts than in wild-type mice (p < 0.05). Such reduction in ischemic damage and neurological deficits was observed 96 hr after ischemia but not at 24 hr, when iNOS is not yet expressed in wild-type mice. The decreased susceptibility to cerebral ischemia in iNOS knockouts could not be attributed to differences in the degree of ischemia or vascular reactivity between wild-type and knockout mice. These findings indicate that iNOS expression is one of the factors contributing to the expansion of the brain damage that occurs in the post-ischemic period. iNOS inhibition may provide a novel therapeutic strategy targeted specifically at the secondary progression of ischemic brain injury.

Roles of CHOP/GADD153 in endoplasmic reticulum stress

“…Mutations in presenilin-1, which increase the production of bamyloid, were shown to increase CHOP protein, using presenilin-1 mutant knockin mice. 97 Increased CHOP was suggested to contribute to the pathogenesis of presenilin-1 mutations by sensitizing neuronal cells to apoptosis. 97 However, concerning the role of presenilin-1 in the ER stress pathway, the question of whether or not presenilin-1 mutations downregulate induction of BiP and CHOP is still being debated.…”

“…97 Increased CHOP was suggested to contribute to the pathogenesis of presenilin-1 mutations by sensitizing neuronal cells to apoptosis. 97 However, concerning the role of presenilin-1 in the ER stress pathway, the question of whether or not presenilin-1 mutations downregulate induction of BiP and CHOP is still being debated. 98,99 Therefore, it remains to be studied whether CHOP induction and ER stress-mediated apoptosis occur in the development of Alzheimer's disease.…”

Targeting Astrocytes for Stroke Therapy

“…27 More typically, a delayed increase in stroke volume is much more subtle or absent in rodent models 13,28,29 ; however, a notable increase in infarct growth may be observed when neuroprotective mechanisms are impaired in the brain, an illustration of the tenuous nature of cell viability in the penumbra. 28,29 Factors such as the presence of edema, peri-infarct depolarizations, 30 -32 inflammatory changes, [33][34][35] or the amount of collateral blood flow likely determine the fate of the penumbra. In addition, expression and release of neuroprotective or harmful substances in response to ischemia are also likely determinants of cell death.…”

“…In addition, expression and release of neuroprotective or harmful substances in response to ischemia are also likely determinants of cell death. 13,29,35 Given that astrocytes modulate blood flow, contribute to water homeostasis, participate in inflammatory responses, maintain ion homeostasis, and release a number of substances that may be either neuroprotective or harmful, they undoubtedly contribute to determining the viability of this vulnerable tissue.…”

S-Nitrosylation and uncompetitive/fast off-rate (UFO) drug therapy in neurodegenerative disorders of protein misfolding

“…Analyses of mice deficient in either nNOS or iNOS confirmed that NO is an important mediator of cell injury and death after excitotoxic stimulation; NO generated from nNOS or iNOS can be detrimental to neuronal survival during various types of insult. 32,33 In addition, inhibition of NOS activity ameliorates Figure 1 Activation of the NMDA receptor (NMDAR) by glutamate (Glu) and glycine (Gly) induces Ca 2 þ influx and consequent NO production via activation of nNOS. nNOS is part of a protein complex attached to the NR1 subunit of the NMDA receptor via binding of its PDZ domain to postsynaptic density protein (PSD-95).…”