Abstract
TBN, a novel tetramethylpyrazine derivative armed with a powerful free radical-scavenging nitrone moiety, has been reported to reduce cerebral infarction in rats through multi-functional mechanisms of action. Here we study the therapeutic effects of TBN on non-human primate model of stroke. Thirty male Cynomolgus macaques were subjected to stroke with 4 hours ischemia and then reperfusion. TBN were injected intravenously at 3 or 6 hours after the onset of ischemia. Cerebral infarction was examined by magnetic resonance imaging at 1 and 4 weeks post ischemia. Neurological severity scores were evaluated during 4 weeks observation. At the end of experiment, protein markers associated with the stroke injury and TBN treatment were screened by quantitative proteomics. We found that TBN readily penetrated the blood brain barrier and reached effective therapeutic concentration after intravenous administration. It significantly reduced brain infarction and modestly preserved the neurological function of stroke-affected arm. TBN suppressed over-expression of neuroinflammatory marker vimentin and decreased the numbers of GFAP-positive cells, while reversed down-regulation of myelination-associated protein 2′, 3′-cyclic-nucleotide 3′-phosphodiesterase and increased the numbers of NeuN-positive cells in the ipsilateral peri-infarct area. TBN may serve as a promising new clinical candidate for the treatment of ischemic stroke.
Highlights
Been a methodologically sound clinical trial demonstrating its benefit
At one week post-surgery, TBN treatment administered at 3 h post-ischemia caused a reduction in overall infarct size in a dose-dependent manner as measured by T2-weighted magnetic resonance imaging (MRI) scans (Fig. 1A,B)
Researchers hope that monkey data will advance the field of stroke therapy with neuroprotective agents
Summary
The exact mechanisms of action of TMP have not been completely understood, a variety of mechanisms may be attributed to its beneficial effects in stroke patients, including inhibiting platelet aggregation, lysing blood clots, blocking intracellular calcium entry and scavenging free radicals[12]. A multi-functional mechanisms possibly contributed to TBN’s beneficial effects in stroke models, including directly scavenging various free radicals, blockade of calcium entry and inhibition of platelet aggregation[16]. To bridge the biological gap between the rodent animal experiments and clinical trials, in the present study, we investigated the therapeutic efficacy of TBN in non-human primate (NHP) model of ischemic stroke, as well as its pharmacokinetics, fulfilling the requirements for initiating investigational new drug application
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