Establishment of ischemia-reperfusion model in male cynomolgus macaques and effects of piceatannol-3'-O-β-D-glucopyranoside injection intervention.

BACKGROUND

Cerebral ischemia is characterized by high incidence, mortality, and disability rates, posing a significant threat to human health. However, current clinical practice lacks effective drugs to mitigate cerebral ischemia-reperfusion injury. Piceatannol-3'-O-β-D-glucopyranoside (PG), an active compound isolated from Rheum lhasaense A.J.Li et P.K.Hsiao, has demonstrated neuroprotective effects in MCAO rats in previous studies. Due to significant differences in brain structure and metabolism between rodents and humans, primates with high homology to humans were selected to further validate the neuroprotective effects, thereby reducing the risks associated with clinical trials. Additionally, given the limitations of scale-based assessments in clinically evaluating cerebral ischemia-reperfusion injury (CIRI) and the influence of the placebo effect in double-blind trials-both of which introduce subjective variability that may underestimate the actual efficacy of the test drug-we also provided objective support for clinical trials by incorporating findings from the exploration of serum biomarkers.

METHODOLOGY: Fifteen male cynomolgus monkeys were subjected to 4 h ligation of the left middle cerebral artery followed by reperfusion before being randomly assigned to three groups. The three groups were intravenously administered physiological saline, PG (4mg/kg) or Edaravone (6 mg/kg) once daily for 15 days. Neurological impairment was evaluated using upper extremity feeding skill tests and neurological function assessments. Furthermore, the volume of brain injury (edema volume and cerebral ischemia volume) was statistically analyzed. Serum biomarkers related to neuronal injury, blood-brain barrier injury, and behavior were detected by ELISA. Immunohistochemistry was performed to examine MMP-9 protein expression in the indicated groups.

RESULTS

After 15 days of daily treatment, the neurological deficit score decreased by 60%, the food grasp success rate increased by 52.9%, and the brain injury volume was reduced by 32.7% in the PG group. Furthermore, PG reduced serum levels of S100β (-18.4%), NSE (-12.2%) and IL-6(-13.8%) while regulating the balance of MMP-9/TIMP-1 in CIRI male cynomolgus monkeys. Immunohistochemistry results indicated that PG suppressed MMP-9 protein expression in CIRI cynomolgus monkeys.

CONCLUSIONS

PG injection exhibits neuroprotective effects in male cynomolgus macaques with CIRI, supporting further clinical trials.