Sodium oligomannate reduces cerebral infarction and improves neurological function through microbiota remodeling in MCAO/R rats.

BACKGROUND

Ischemic stroke is the second leading cause of death worldwide, characterized by high mortality and a narrow therapeutic window for thrombolysis. Gut microbiota dysbiosis and gliosis following ischemic stroke are key drivers of post-stroke neurological impairment. Sodium oligomannate (GV-971) is a low-molecular-weight acidic oligosaccharide that targets the gut-brain axis. It alleviates gliosis and improves cognitive dysfunction by remodeling gut microbiota in Alzheimer's disease. However, it is still unknown whether GV-971 has pharmacological activity against ischemic stroke.

METHODS

Here, we explore the efficacy of GV-971 on infarct volume, gliosis, blood-brain barrier integrity, gut microbiota composition, and post-stroke cognitive impairment (PSCI) using a middle cerebral artery occlusion/reperfusion (MCAO/R) model in male Sprague-Dawley rats.

RESULTS

Administer medication before surgery for 4 consecutive days and once after surgery, after stroke 24-hour triphenyltetrazolium chloride (TTC) staining revealed that 0.3 mg/kg GV-971 significantly reduced infarct volume in ischemic brain tissue from 37.81±2.391% to 13.30±4.801% and neurological impairment score of GV-971 treatment significantly decreased from 11.50±0.54 to 7.29±1.47. After stroke 24-hour immunofluorescence analysis of glial activation confirmed that GV-971 significantly reduced central inflammatory responses. Western blot combined with Evans blue staining collectively demonstrated that after stroke 24-hour, GV-971 exerts a significant protective effect on the blood-brain barrier. In the gut, GV-971 reversed microbial dysbiosis, as revealed by shotgun metagenomics, enhanced intestinal barrier integrity, and suppressed colonic inflammation. Antibiotic depletion abolished GV-971's neuroprotective effect, while fecal microbiota transplantation from GV-971-treated donors restored protection, supporting a microbiota-dependent contribution. Furthermore, GV-971-treated rats subjected to MCAO/R exhibited significant improvements in motor and cognitive function. For example, on day 35, Y-maze test results indicated that GV-971 administered either before MCAO/R (pre-treatment) or during the perioperative period (co-treatment) increased spontaneous alternation rate from 60.95±4.91% to 85.60±6.32% and 85.64±5.027%. On day 32, novel object recognition assay results indicated that GV-971 treatment increased new-object exploration from 0.2039±0.03752 to 0.3991±0.1122 (pre-treatment) and 0.5066±0.06982 (co-treatment). On day 42, Barnes maze test results indicated that GV-971 treatment reduced the time required to locate the target hole from 76.45±17.41s to 31.03±20.75 s and 33.37±19.30 s for pre- and co-treatment, respectively.

CONCLUSION

Taken together, GV-971 demonstrated neuroprotective potential in experimental ischemic stroke.