Elucidating effects of alpiniae oxyphyllae fructus and its active compounds on improving spatial cognitive function via brain-derived neurotrophic factor signaling pathway in post ischemic stroke treatment

Abstract

Stroke is a major disease burden with high mortality and disability caused by impeded blood flow to the brain, but the drug candidate for post-stroke brain repairing is needed to be explored. Adult neurogenesis provides regenerative resources and opportunities for post-stroke brain repairing. Brain-derived neurotrophic factor is an important neurotrophic factor to promote neurogenesis in the hippocampal region. It shows relevant participation in memory formation, which can be an important therapeutic target for drug exploration in improving stem cell transplantation to enhance neurological function recovery and adult treatment in post-stroke treatment. Alpiniae Oxyphyllae Fructus (AOF) is a traditional medicinal herb that is commonly used in post-stroke treatment, but the underlying mechanisms and bioactive compounds for neuroprotective and neurogenic effects remain unclear.

In this study, the hypotheses that whether AOF and its active compounds could induce adult hippocampal neurogenesis and improve post-stroke cognitive impairment via inducing brain-derived neurotrophic factor (BDNF) signaling pathway, both in in vivo rat model of transient middle cerebral artery occlusion (MCAO) ischemia and in vitro cultured neural stem cells (NSCs) under oxygen-glucose deprivation (OGD)/reoxygenation condition was certified. Network pharmacology analysis were used to explore the molecular mechanisms of AOF in the treatment of the ischemic stroke. According to the results from the Morris water maze test (MWM) and novel objective recognition test (ORT), AOF treatment was found to significantly enhance the spatial learning/memory and cognitive capacities in post-ischemic stroke rats and reduce anxiety in the open field test. AOF promoted adult neurogenesis in the hippocampus and up-regulated expression level of BDNF, TrkB and p-Akt in the hippocampal regions.

By high-performance liquid chromatography (HPLC) and Liquid chromatography–mass spectrometry (LC-MS), the compounds were identified in AOF. Combined with high-content screening (HCS) technology, p-coumaric acid (P-CA) was identified as the most active ingredient from AOF to induce proliferation of NSCs and activate the BDNF/TrkB/Akt pathway. The effects of P-CA on inducing BDNF/TrkB/Akt signaling and the NSCs proliferation were abolished by ANA12, a BDNF/TrkB specific inhibitor. Furthermore, P-CA enhanced NSCs proliferation and differentiation in the hippocampus, improved learning function, increased short and long-term memory, and reduced anxiety in the post MCAO ischemic rats.

On the other hand, P-CA treatment promoted the survival of primary hippocampal neurons after OGD and showed neuroprotective effect on hippocampal neurons from OGD damage via the mediation of BDNF/TrkB/Akt signaling pathway. The molecular docking score of P-CA with protein BDNF was -4.61 kcal/mol, which proved the close binding of the ligand with protein.

Taken together, I conclude that P-CA is a representative active compound from AOF to promote hippocampal neurogenesis, enhance cognitive functions, and reduce anxiety for post-ischemic stroke. The underlying mechanisms might be related to the medication in activating the BDNF/TrkB/Akt signaling pathway.