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NOS knockout or inhibition but not disrupting PSD-95-NOS interaction protect against ischemic brain damage.


ABSTRACT: Promising results have been reported in preclinical stroke target validation for pharmacological principles that disrupt the N-methyl-D-aspartate receptor-post-synaptic density protein-95-neuronal nitric oxide synthase complex. However, post-synaptic density protein-95 is also coupled to potentially neuroprotective mechanisms. As post-synaptic density protein-95 inhibitors may interfere with potentially neuroprotective mechanisms and sufficient validation has often been an issue in translating basic stroke research, we wanted to close that gap by comparing post-synaptic density protein-95 inhibitors with NOS1(-/-) mice and a NOS inhibitor. We confirm the deleterious role of NOS1 in stroke both in vivo and in vitro, but find three pharmacological post-synaptic density protein-95 inhibitors to be therapeutically ineffective.

SUBMITTER: Kleinschnitz C 

PROVIDER: S-EPMC5012526 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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NOS knockout or inhibition but not disrupting PSD-95-NOS interaction protect against ischemic brain damage.

Kleinschnitz Christoph C   Mencl Stine S   Kleikers Pamela W M PWM   Schuhmann Michael K MK   López Manuela G MG   Casas Ana I AI   Sürün Bilge B   Reif Andreas A   Schmidt Harald H H W HHHW  

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160628 9


Promising results have been reported in preclinical stroke target validation for pharmacological principles that disrupt the N-methyl-D-aspartate receptor-post-synaptic density protein-95-neuronal nitric oxide synthase complex. However, post-synaptic density protein-95 is also coupled to potentially neuroprotective mechanisms. As post-synaptic density protein-95 inhibitors may interfere with potentially neuroprotective mechanisms and sufficient validation has often been an issue in translating b  ...[more]

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