Novel neuroprotectant successful in stroke models
MedWire News: Researchers have developed a novel neuroprotectant that reduces cerebral ischemic damage in rodents after stroke, they report in Nature Medicine.
The molecule is designed to inhibit the interaction between neuronal nitric oxide synthase (nNOS) and the scaffolding protein postsynaptic density protein (PSD)-95.
PSD-95 binds nNOS and N-methyl-D-aspartate receptors (NMDARs), assembling them into macromolecular signaling complexes and resulting in the activation of nNOS.
Dong-Ya Zhu (Nanjing Medical University, China) and colleagues show that nNOS-PSD-95 complexes are increased in the cortices of mice subjected to cerebral ischemia and reperfusion.
This was not caused by increased nNOS expression, they say; instead ischemia appeared to cause a shift from the cytosolic (soluble) to the membrane-bound form of nNOS. The process was dependent on NMDAR activation.
Previous research has suggested a role for nNOS in glutamate-mediated neuronal death, and neurons lacking nNOS, or PSD-95, show reduced vulnerability to excitotoxicity, say Zhu et al.
In the current study, the researchers successfully blocked the nNOS-PSD-95 interaction using a vector that expressed a select region of nNOS that is crucial for its binding to PSD-95. Pretreating mice with this vector significantly reduced stroke damage.
The team then developed several molecules designed to disrupt nNOS-PSD-95 interaction. The most potent of these, named ZL006, significantly reduced infarct sizes and improved neurologic outcomes in mice when given up to 3 hours after cerebral ischemia and reperfusion.
ZL006, given 1 hour after reperfusion, was also effective in rats. In normal rats, the molecule readily crossed the blood-brain barrier, and had no notable adverse effects.
The researchers say that selective inhibition of NMDARs and nNOS produces severe adverse effects, including cognitive problems, hallucinations, and coma for the former, and impaired learning and memory, and aggressive behavior for the latter.
"ZL006 did not inhibit nNOS catalytic activity and NMDAR function, and it had no effect on aggressive behavior and spatial memory," say Zhu and team.
"Thus, this drug may treat stroke without major side effects."
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By Eleanor McDermid