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Assessing Neuroprotective Effects of Glycyrrhizae Radix et Rhizoma Extract Using a Transient Middle Cerebral Artery Occlusion Mouse Model
Published on: December 9, 2018
Sodium oligomannate reduces cerebral infarction and improves neurological function through microbiota remodeling in
Jin Han1,2, Wei Zhao1,2, Rui Deng1,2
1School of Pharmacy, Anhui University of Chinese Medicine, Hefei, China.
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.
Insights
Sodium oligomannate (GV-971) significantly reduces brain infarct volume and neurological deficits in ischemic stroke models. This gut-brain axis agent restores gut microbiota balance and improves cognitive function, demonstrating neuroprotective potential.
Area of Science:
- Neuroscience
- Pharmacology
- Microbiology
Background:
- Ischemic stroke is a leading cause of death with limited treatment options.
- Gut microbiota dysbiosis and gliosis contribute to neurological impairment post-stroke.
- Sodium oligomannate (GV-971) targets the gut-brain axis, improving cognition in Alzheimer's disease.
Purpose of the Study:
- To investigate the efficacy of GV-971 in an experimental ischemic stroke model.
- To assess GV-971's effects on infarct volume, gliosis, and blood-brain barrier integrity.
- To evaluate GV-971's impact on gut microbiota and post-stroke cognitive impairment.
Main Methods:
- Middle cerebral artery occlusion/reperfusion (MCAO/R) model in Sprague-Dawley rats.
- GV-971 administration before and after MCAO/R.
- Assessment of infarct volume, neurological scores, glial activation, and blood-brain barrier integrity.
- Shotgun metagenomics for gut microbiota analysis, intestinal barrier function, and inflammation assays.
- Behavioral tests including Y-maze, novel object recognition, and Barnes maze for cognitive function.
Main Results:
- GV-971 significantly reduced infarct volume and neurological impairment.
- Treatment decreased glial activation and protected blood-brain barrier integrity.
- GV-971 reversed gut microbial dysbiosis, enhanced intestinal barrier function, and reduced colonic inflammation.
- Neuroprotection was dependent on gut microbiota, as evidenced by antibiotic depletion and fecal microbiota transplantation studies.
- GV-971 significantly improved motor and cognitive functions in MCAO/R rats.
Conclusions:
- GV-971 demonstrates significant neuroprotective potential in experimental ischemic stroke.
- The therapeutic effects of GV-971 are mediated through the gut-brain axis and gut microbiota modulation.
- GV-971 represents a promising therapeutic agent for ischemic stroke treatment.
