|Year : 2019 | Volume
| Issue : 2 | Page : 104-115
Active compounds and molecular targets of Chinese herbal medicine for neurogenesis in stroke treatment: Implication for cross talk between Traditional Chinese Medicine and Biomedical Sciences
Xi Chen1, Han-Sen Chen2, Cheng Peng3, Jian-Gang Shen4
1 School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR; Department of Core Facility, The People's Hospital of Bao-an, cDepartment of Core Facility, The 8th People's Hospital of Shenzhen, The Affiliated Baoan Hospital of Southern Medical University, Chengdu, China
2 School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
3 College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Sichuan Province and Ministry of Science and Technology, Chengdu, China
4 School of Chinese Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR; Department of Core Facility, The People's Hospital of Bao-an, China
|Date of Submission||28-Sep-2018|
|Date of Acceptance||07-Apr-2019|
|Date of Web Publication||20-Jun-2019|
School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam, Hong Kong, Hong Kong SAR
Source of Support: None, Conflict of Interest: None
Neural stem/progenitor cells (NSCs) could be attractive therapeutic targets for promoting adult neurogenesis, brain plasticity, and repair in stroke and neurodegenerative diseases, raising great potentials for regeneration therapy. In adult ischemic brains, NSCs have limited capacities of growth, differentiation, and generating new neurons for repairing the damaged central nervous system. However, the spontaneous brain repair seems to be insufficient to recover neurological deficits in most stroke cases. To overcome those problems, pharmacological manipulations targeting on endogenous NSCs or transplanted stem cells could be a promoting strategy for regeneration therapy. Chinese herbal medicine has great potentials for developing novel therapeutic strategies for adult neurogenesis and brain repair in poststroke treatment. Chinese herbal medicine has a long history for poststroke treatment. Recent studies create great opportunity for drug discovery for promoting neurogenesis and improving the recovery of neurological functions in poststroke treatment. Many active compounds or extracts from medicinal herbs have shown promising effects on regulating proliferation, self-renewal and differentiation of NSCs, and promoting neural network formation as well as neurological functional recovery with in vitro and in vivo experimental evidence. Therefore, targeting neural stem/progenitor cells can be an important opportunity for the studies of Traditional Chinese Medicine in regeneration medicine. Due to the complex interactions of herbal ingredients in network regulation, huge challenge remains to be resolved for further study.
Keywords: Chinese herbal medicine, neurogenesis, stroke
|How to cite this article:|
Chen X, Chen HS, Peng C, Shen JG. Active compounds and molecular targets of Chinese herbal medicine for neurogenesis in stroke treatment: Implication for cross talk between Traditional Chinese Medicine and Biomedical Sciences. World J Tradit Chin Med 2019;5:104-15
|How to cite this URL:|
Chen X, Chen HS, Peng C, Shen JG. Active compounds and molecular targets of Chinese herbal medicine for neurogenesis in stroke treatment: Implication for cross talk between Traditional Chinese Medicine and Biomedical Sciences. World J Tradit Chin Med [serial online] 2019 [cited 2020 Feb 19];5:104-15. Available from: http://www.wjtcm.net/text.asp?2019/5/2/104/260847
| Introduction|| |
Stroke is the second leading disease of mortality and a leading cause of adult disability according to the WHO report., In China, the age-adjusted stroke prevalence ranges from 259.86 to 719 per 100,000 people per year. Ischemic stroke caused by vessel occlusions accounts for 85% of all stroke patients. With rapid degeneration of brain structure following the functional neuronal loss, ischemic stroke patients suffer from several neurological dysfunctions, inducing paralysis, loss of speech, loss of vision, and trouble in balance or coordination and coma.
Under ischemic stroke conditions, the core of ischemic brain tissue undergoes necrotic cell death within a few minutes after cerebral ischemia. Early restoration of blood flow by thrombolytic therapy is an essential strategy to reduce morbidity and mortality in these patients. Paradoxically, recanalization for reperfusion, such as thrombolytic treatment with recombinant tissue-plasminogen activator (rt-PA), evokes additional brain injury to ischemic penumbra, a region bordering the ischemic infarct core. Cerebral ischemia-reperfusion (I/R) injury exacerbates neuronal cell death and blood-brain barrier (BBB) damage, and increases the severity of morbidity in surviving victims. As the only FDA approved thrombolytic reagent, rt-PA is an effective drug for recanalization of the ischemic brains but has restrictive therapeutic time within 4.5 h after onset of ischemic stroke. Although early thrombolytic therapy could decrease morbidity and mortality, most of the patients could not catch up the golden window. Treated beyond the 4.5 h, ischemic stroke patients had the tenfold increases of the risk of hemorrhagic transformation (HT) and the increased morbidity and mortality., Limited therapy is available for poststroke rehabilitation and improving recovery of neurological deficits, leading most stroke victims long-term disability.
Recent progress in regeneration therapy brings new hopes for the treatment of poststroke disability as well as other neurodegenerative diseases. Endogenous adult neurogenesis is an important direction for regeneration therapy., Adult spontaneous neurogenesis mainly occurs in the subgranular zone in the dentate gyrus (DG) of the hippocampus (HIP) and subventricular zone (SVZ) adjacent to the lateral ventricle (LV)., Enhanced neurogenesis has been reported in different experimental systems including ischemic brains of neonatal mice, adult rats, and aged humans in vivo.,,, Nevertheless, the spontaneous neurogenesis fails to recover neurological function in ischemic stroke patients. Recent progress in clinical trials indicates that stem/progenitor cell transplantation could be an attractive brain repair strategy for poststroke treatment.,,, Development of stem cell therapy strategies for regeneration medicine is timely important for stroke treatment.
Traditional Chinese Medicine (TCM) has been used for centuries in China, Korea, Japan, as well as other Asian countries for the treatment of the diseases characteristically clinical symptoms and statuses similar to cerebrovascular diseases including dizziness, paralysis, loss of speech, loss of vision, coma and dementia. With over 2000-year practice, TCM accumulates many medicinal herbs and TCM formulas and histological documents about the theory and practices of TCM for stroke treatment. Last decades, large effects were made to understand the therapeutic principles of Chinese herbal medicine and acupuncture and explore the applications of TCM formula, single herbal extractions, and pure compounds for regenerative therapy. In the present study, we focus on the pure compounds and/or extracts of commonly used Chinese medicinal herbs for promoting neurogenesis and analyze the future development of Chinese Medicine targeting stem cell therapy for brain repair in poststroke treatment.
| Traditional Chinese Medicine Theory for Poststroke Treatment|| |
With its long history, TCM accumulates huge histological documents for understanding the pathological basis of stroke and therapeutic approaches. Stroke is defined as “Wind Stroke” in TCM. “Wind Stroke” refers to the syndrome conditions characterized by a sudden collapse, loss of consciousness, deviation of the tongue and mouth, hemiplegia, slurred speech, or only deviation of the tongue and mouth and hemiplegia without collapses. The pathogens and therapeutic approaches of “Wind Stroke” date back to the Han Dynasty described in “Treatise on Cold Damage (Shang Han Lun)” and “Synopsis of the Golden Chamber (Jin Kui Yao Lue).” The pathological basis of “Wind Stroke” was attributed to the “Wind Stroke Attacking due to Collateral Deficiency.” “Wind Stroke” is considered as the consequences of Zang-fu and Meridian dysfunctions and Qi-Blood disruption due to the accumulations of abnormal diet and lifestyles, psychological stress, and mental disorders, etc., The pathogens of the “Wind Stroke” are complex. The core pathological basis of the “Wind Stroke” can be attributed to the dysfunctions of Zhang-fu and Meridian, which eventually leads to cerebral thrombosis or cerebral hemorrhage. The deficiency of Qi-Blood and imbalance of Yin-Yang are the basis of attacking of “Wind Stroke.” The pathological factors or statuses, including Qi Stagnation, Blood Stasis, Wind Invasion, Liver Fire, Phlegm Accumulation, Deficiency of Qi-Blood and Yin-Yang, contribute to the neurological dysfunctions and cognitive impairments in the “Wind Stroke” patients. According to TCM theory, “Wind Stroke” has several different clinical patterns catalyzed “Meridian stroke,” “Zhang-fu stroke,” and sequela. “Meridian stroke” is defined as the clinical pattern with only deviation of the tongue and mouth and hemiplegia without collapses and loss consciousness, whereas “Zhang-fu stroke” would be accompanied by obnubilation. Thus, the pathology of the “Wind Stroke” is correlated with the dysfunctions of Zang-fu and Meridian and the disruption of Qi-blood and Yin-Yang. Restoring the dynamic balances of Qi-blood and Yin-yang is an essential principle for stroke treatment. With 1000-year accumulation, many medicinal herbs and classical TCM formulas have potentials for the treatment of poststroke disability. The accumulated knowledge and histological documents from direct experience in human subjects are important sources for regeneration medicine. Recent years, large efforts have been made to explore the scientific basis of Chinese medicinal herbs for poststroke treatment. With the progress of stem cell biology and regeneration medicine, many frontier technologies and methods have been developed, greatly facilitating the studies of the therapeutic principles of Chinese herbal medicine for poststroke treatment. Several years ago, we reviewed the progress of Chinese herbal medicine for promising neurogenesis.,, Recently, more and more research articles have been published, bringing better understanding the therapeutic principles and active compounds of medicinal herbs for promoting neurogenesis in poststroke treatment. In this mini-review, we specially focus on the relationship between the traditional therapeutic functions of Chinese medicinal herbs and the bioactivities of those herbs and their active compounds for promoting adult neurogenesis. We hope to provide cross talk between TCM and biomedicine for regeneration therapy in poststroke treatment.
| Current Progress of Chinese Herbal Medicine for Promoting Neurogenesis and Their Molecular Targets for Poststroke Treatment|| |
Recent years, extensive efforts have been made to verify the therapeutic outcome of TCM approaches and explore the underlying mechanisms and molecular targets for their neuroprotection and neurogenesis-promoting effects. Many TCM formulae, single herbs or pure compounds revealed their bioactivities to promote neuronal survival and neurite growth and facilitate neurological functional recovery via targeting different cellular signaling pathways in different experimental systems. Interestingly, those herbs and TCM formulae are generally in the catalog lists of the medicinal herbs with the properties of Removing Blood-stagnation and/or Phlegm Accumulation to Improve Qi-Blood Movement in Meridian, or Tonifying Zang-fu Functions for Resolving Qi-Blood and Yin-Yang Deficiency according to classical TCM theory. The cross talking between TCM and modern biomedical sciences provide a unique opportunity for better understanding the ancient therapeutic arts and brings novel ideas for drug discovery in regeneration therapy. In this session, we reviewed the update progress on the studies of the active compounds, herbal extracts, and TCM formulas with potentials for promoting neurogenesis and their relevant molecular targets and mechanisms [Table 1].
Neurogenesis-promoting effects of Medicinal Herbs used for Resolving Blood Stasis
According to TCM theory, the Blood Stasis is a common syndrome pattern in ischemic stroke patients, and subsequently, the therapeutic strategy for promoting blood circulation is widely used to treat the disability of ischemic stroke patients in TCM practice. Many studies suggest that the neurogenesis-promoting effects of medicinal herbs with the properties of improving blood circulation could be important sources for poststroke treatment.
Salvia miltiorrhiza, named Danshen in Chinese, is commonly used for stroke with anti-oxidative, anti-inflammatory, and anti-apoptotic properties. S. miltiorrhiza could improve the differentiation of induced pluripotent stem cell (iPSCs) into neuronsin vitro and promote the survival, integration, and differentiation of the iPSCs-derived neural stem cell after their transplantation into the ischemic brain tissues. S. miltiorrhiza treatment effectively promoted the survival of grafted MAP2(+) cells in the ischemic brains after cells transplantation at 7 days and enhanced functional recovery at 7 and 14 days.S. miltiorrhiza also promoted the proliferation and differentiation of bone marrow-derived neural stem cells (BM-NSCs) into NF-M(+) neurons and NG2(+) oligodendrocyte precursors but reduced the formation of GFAP(+) astrocytes. Salvianolic acid B (Sal B) had neuroprotective effects on BM-NSCs upon exposure to H2O2. Sal B is a representative active compound from Danshen with antioxidant, anti-inflammatory, antiapoptotic, and neuroprotective properties. Sal B revealed its neuroprotective effects on protecting iPSCs-derived NSCs against H2O2-induced neural injury. Tanshinone II A (TIIA) is another representative bioactive compound from Danshen. In our previous study, TIIA dose-dependently promoted neuronal differentiation in three different stem cells, including immortalized C17.2 NSCs, rat embryonic cortical NSCs, and rat PC12 pheochromocytoma cells. The underlying mechanisms could be related to regulating mitogen-activated protein kinase (MAPK) 42/44 mediated brain-derived neurotrophic factor (BDNF) and NGF signals in a caveolae-dependent manner. Similarly, Sal B was reported to promote neural differentiation of iPSCs via regulating phosphatidylinositol 3-kinase (PI3K)/AKT/G SK3 β/β-catenin pathway. Those studies suggest that S. miltiorrhiza and its active compounds have the potentials for inducing adult neurogenesis from different sources of stem cells for regeneration therapy.
Ligusticum walliichi, named Chuanxiong in Chinese, is an important medicinal herb with functions of promoting blood circulation and widely used for the treatment of ischemic stroke. Tetramethylpyrazine (TMP) is an active compound isolated from Chuanxiong. A recent study showed that TMP promoted the migration of neural progenitor cells (NPCs) toward the ischemic region in the middle cerebral artery occlusion rat model via inducing the expression and secretion of stromal cell-derived factor 1, a chemokine for guiding NPCs trafficking. TMP treatment rapidly activated PI3K/Akt, protein kinase C, and extracellular signal-regulated kinase (ERK), but not Pyk2, in NPCs. Anotherin vitro study revealed that TMP promoted SH-SY5Y cells to differentiate toward postmitotic neurons by the epigenetic regulation of topoisomerase Iiβ (TopoIIβ), a nuclear enzyme for neuronal development. TMP could be a promising compound for inducing the growth, development, and migration of endogenous NSCs for brain repair. Those studies provide a cue for better understanding the therapeutic principles of Chuanxiong and exploring its representative active ingredients for poststroke treatment.
Radix Angelica Sinensis (RAS, Dangui in Chinese) is another representative Chinese herbal medicine, with the properties of promoting blood circulation to dispel blood stasis and used for ischemic stroke treatment. RAS has potentially beneficial effects for the patients suffering from cognitive impairment associated with chronic cerebral hypoperfusion. RAS treatment enhanced adult HIP neurogenesis and improved the cognitive functions after chronic cerebral hypoperfusion through inducing BDNF and phosphorylated cyclic adenosine monophosphate (cAMP)-responsive element binding protein as well as increasing γ-aminobutyric acid expression.
Panax notoginseng, named Sanqi in Chinese, is another typical medicinal herb to promoting blood circulation for removing blood stasis. A recent study investigated the effects of P. notoginseng saponins (PNS) on the proliferation, differentiation, and self-renewal of rat embryonic NSCs. PNS promoted rat embryonic cortical NSCs survival, self-renewal, proliferation, and differentiation through promoting autocrine or paracrine of neurotrophic factors such as basic fibroblast growth factor and BDNF in rat embryonic NSCs. Total saponins of P. notoginseng promoted differentiation of doublecortin(+) cells expressing immature neuroblasts in the olfactory bulb (OB) via activating cAMP response element binding protein in postischemia/reperfusion brains. Ginsenoside Rg1 is a representative active ingredient of Panax ginseng. Ginsenoside Rg1 revealed its neuroprotective effects on the HIP in the D-gal (D-galactose) induced aging rat model. Ginsenoside Rg1 treatment improved cognitive functions, protected NSCs/NPCs, and promoted neurogenesis. The underlying mechanisms could be related to enhancing the antioxidant and anti-inflammatory capacity in the HIP. Ginsenoside Rg1 treatment also revealed to promote the proliferation and glial-like-directed differentiation of cortical NSCs.
Oxidative stress and redox signaling play important roles in regulating neurogenesis. The antioxidant property of the active compounds could be important for promoting neurogenesis. A recent study compared the neuroprotective effects of the different ginsenosides, including Rb1, Rd, Rg1, and Re on the cultured NPCs in the tert-Butylhydroperoxide (t-BHP)-induced oxidative stress model. Only Rb1 treatment attenuated tBHP toxicity in the NPCs by modulating the nuclear factor (erythroidderived 2) like 2/heme oxygenase1 pathway as well as activating Nrf2 pathway. Therefore, the neuroprotective and neurogenic effects of PNS and its active compounds Rg1 and Rb1 are valuable for further investigations to confirm their activities in regeneration therapy.
Neurogenesis-promoting effects of Medicinal Herbs for Removing Phlegm Accumulation
According to TCM theory, Phlegm accumulation is one of the critical pathological factors contributing to the cognitive deficit and neurological dysfunctions in different types of Wind Stroke including “Meridian stroke,” “Zhang-fu stroke,” and sequela. Removing Phlegm Therapy is an important therapeutic strategy to improve the recovery of cognitive and other neurological functions. Ginkgo biloba is a typical medicinal herb for removing phlegm accumulation in TCM practice. EGb761 is a standard extract from G. biloba as functional health supplement for improving memory loss and cognitive impairments in stroke, senile dementia, and Parkinson's disease patients. EGb761 revealed to enhance NSCs proliferation in the SVZ and DG and promoted learning and memory in rats with vascular dementia.Polygala tenuifolia Willd (PTW), named Yuanzhi in Chinese, is a representative medicinal herb with the properties of removing phlegm and promoting resuscitation of cognitive impairment according to the TCM concept. PTW has been commonly used for improving cognitive impairment for postischemic stroke in TCM practice. Tenuigenin, an active ingredient of PTW, showed to promote the proliferation and differentiation of hippocampal NSCs in vitro. Interestingly, PTW is simultaneously used with Rhizoma Acori tatarinowii (RAT, Shichangpu in Chinese) as a paired herbal group for removing phlegm and promoting resuscitation of cognitive impairment clinically. The neurogenesis-promoting effects of the RAT's active components have been reported as well. Oral administration of RAT extract and its active constituent asarones enhanced NPCs proliferation and neurogenesis in the hippocampi of adult and aged mice as well as transgenic Alzheimer's disease (AD) model mice. RAT and asarones activated ERK signaling cascades for inducing neurogenesis. Those studies provide promising experimental evidence to elucidate the active compounds of PTW and RAT and their potential molecular targets for the improvement of brain repairs in poststroke treatment. However, experimental evidence is still lack to elucidate whether the paired herbal group of PTW and RAT would have better synergic effects than the individual herbal item on inducing neurogenesis and promoting the recoveries of neurological dysfunctions and cognitive impairments in poststroke treatment.
Neurogenesis-promoting effects of Medicinal Herbs for Removing Internal Heat for Detoxification
Herbal items with the properties of removing internal heat for detoxification are commonly used at the acute and subacute statuses in both ischemic stroke and hemorrhagic stroke for anti-inflammation and improving cognitive functions in TCM practice. Whether the herbs for removing internal heat and detoxification have neurogenetic promotive effects is an interesting question. Radix scutellaria (Huangqin) and Radix phellodendri (Huangbo) are two representative herbs with the functions for removing internal heat and detoxification. Oral administration of those herbs reversed the elevation of plasma corticosterone levels and body weight loss and depressive behaviors in chronic mild stress-induced depression-like mouse model, and the anti-depressive mechanisms could be related to the inhibition of hypothalamic-pituitary-adrenal (HPA) axis hyperactivity and the increasing of hippocampal precursor cell proliferation. Our previous study revealed that Baicalin can directly scavenge superoxide and react with peroxynitrite, inhibited the formation of 3-nitrotyrosine, reduced infarct size, and attenuated apoptotic cell death in cerebral I/R injury. Our recent study further revealed that baicalin protected the blood–brain-barrier (BBB) integrity and prevented HT and neurotoxicity in postischemic brain injury with the delayed t-PA treatment. On the other hand, we found that baicalin-regulated cell fate decision in embryonic NPCs by promoting neural differentiation but inhibiting glial formation in cultured embryonic NPCs. The underlying mechanisms are related to regulating the signal transducer and activator of transcription 3 and basic helix-loop-helix signal pathways. Other independent group also proved that baicalin stimulated the differentiation of human umbilical cord blood mesenchymal stem cells and rat BM stromal cells into neurons. Furthermore, our recent study found that baicalin could modulate APPL2/glucocorticoid receptor signaling cascades, promote neurogenesis in the HIP and SVZ-OB, and subsequently attenuating emotional and olfactory dysfunctions in a chronic corticosterone-induced depression mouse model. Thus, R. scutellaria (Huangqin) and its active compounds like baicalin have great potentials as neurogenic promoters for brain repair in the treatment of poststroke disability and other neurological disorders such as chronic stress-induced depressions.
Neurogenesis-promoting effects of Tonic Medicinal Herbs
Tonifying Qi-Blood and Yin-Yang Strategy is an essential TCM therapeutic principle for poststroke treatment. Many investigations have been conducted to explore the potential therapeutic values of the herbs and their active compounds for brain repair of poststroke disability. Radix astragali (Astragalus menbranaceus Fisch; Huangqi) is the most common used Qi-tonifying Chinese medicinal herb for the treatments of stroke and neurodegenerative diseases. Astragalosides are bioactive components isolated from R. astragali. Astragaloside IV (AS-IV) is one of the representative compounds of Astragalosides, and its neuroprotective effects have been extensively studied. AS-IV revealed its neuroprotective effects against experimental cerebral ischemic injury with different molecular mechanisms. The underlying mechanisms of AS-IV for protecting ischemic brain injury are multiple aspects including antioxidative/nitration stress, anti-inflammation and anti-apoptosis, prevented neutrophils accumulation and inhibited the expression of intercellular adhesion molecule-1, reduced the frequencies of synchronized spontaneous Ca2+ oscillations, and spontaneous excitatory postsynaptic currents in hippocampal neurons. AS-IV treatment protected the BBB integrity by reserving the expression of tight junction proteins such as occludin and zonae occlude-1 in ischemia-reperfused rat brains. A recent study reported that As-IV could activate Nrf2 signaling pathway and subsequently protected the integrity of BBB in LPS-induced mice. In addition to the neuroprotection, AS-IV treatment also enhanced the axonal regeneration and reconstruction of neuronal synapses and prevented Aβ (25–35)-induced neuronal death. AS-IV promoted neurogenesis in the mouse hippocampal DGs, and the underlying mechanisms could be related to modulating the homeostasis of the chemokine (C-X-C motif) ligand 1/C-X-C Motif Chemokine Receptor signaling pathway. Except for AS-IV, Astragalus polysaccharides and Astraisoflavan, the other active ingredients of R. astragali, showed their neurogenesis-promoting effects on promoting the proliferation of NSCs and guiding the committed differentiation of NSCs into dopamine neurons through modulating Sonic hedgehog, orphan nuclear hormone 1, and pituitary homeobox 3 -signaling pathways. Our recent study revealed that Astragaloside VI (AS-VI) had even better neurogenesis-promoting effects than other Astragalosides. AS-VI effectively activated epidermal growth factor receptor/MAPK signaling cascades, promoted proliferation and differentiation of NSCs in transient cerebral ischemic brains and improved the neurological functions in postischemic stroke rats. AS-VI has great potentials to be a drug candidate for regeneration therapy. Those studies not only bring novel insights into the therapeutic principles of R. astragali but also provide the cue for drug discovery in the treatment of poststroke disability.
Herba epimedii is a famous Chinese herbal medicine with the “Yang-tonic” function. Icariin (ICA) is a representative compound isolated from H. epimedii. ICA was previously reported to improve cognitive deficits and activate quiescent NSCs in aging rats. ICA dose-dependently promoted neurosphere formation when the NSCs cultured with the growth protocol. ICA treatment-induced NSCs proliferation but had no effect on NSCs differentiation in differentiation protocol. ICA could activate MAPK pathway for inducing neurogenesis.
Ganoderma lucidum, Linzhi in Chinese, is commonly used food supplement as well as tonic medicinal herb. Oral administration of the polysaccharides and water extract of G. lucidum promoted NPCs proliferation, enhanced neurogenesis, and alleviated cognitive deficits in transgenic AD mice. G. lucidum polysaccharides (GLP) also promoted self-renewal of NPCs via activating fibroblast growth factor receptor 1 and its downstream ERK and AKT cascades. Whether GLP has similar effects on promoting neurogenesis is an interesting topic for further investigation.
Cuscuta japonica Choisy (CJ, tushizi in Chinese) is also an important component in TCM remedies with the tonic functions for treatment of Kidney-Qi and Kidney-Essence Deficiency Syndrome in poststroke disability according to the TCM theory. A recent study investigated the effects of CJ on promoting adult hippocampal neurogenesis and memory function in mice. CJ water extract dose-dependently promoted the proliferation, differentiation, and maturation of NSCs for neurogenesis and improved the cognitive functions in the mice.
Neurogenesis-promoting effects of Wind-dispelling Herbs
According to the TCM therapy, “External Wind Invasion into Meridian and Channel” and “Internal Wind-like Pathological Factors due to Dysfunction of Zang-fu” are two major pathological statuses in “Wind Stroke.” The theory is commonly used for the explanations of the symptoms of neurological deficits such as acute sudden collapse, loss of consciousness, deviation of the tongue and mouth, hemiplegia, and slurred speech. The medicinal herbs with the wind-dispelling properties have been used for the treatment of “Wind Stroke” for 1000 years. Interestingly, the neurogenesis-promoting effects of wind-dispelling herbs and their active ingredients have been reported as well. Angelicae Pubescentis Radix, named Duhuo in Chinese, is a representative herb used in many famous TCM formulas for “Wind Stroke”. Osthole (Ost) is a principal bioactive component of Radix Angelicae Pubescentis. A previous study indicates that Ost protects bone marrow-derived-NSCs (BM-NSCs) against oxidative stress injury, and it can be used to improve the inflammatory environment of neurodegenerative diseases so and promote the survival rate of transplanted NSCs. The study provides a novel idea to use Chinese medicinal herbs for stem cell transplantation in poststroke treatment.
| Discussion|| |
In summary, current studies extensively investigated the effects of Chinese herbal medicine on promoting adult neurogenesis and recovering neurological functions in differentin vitro andin vivo systems. The experimental systems cover almost all stages of the neurogenic process such as proliferation, self-renewal, differentiation, precursors growth, development, and migration of the different types of stem cells. The cell types include BM derived-neural stem cells, pluripotent stem cells, immortalized C17.2 NSCs, embryonic cortical NSCs, and PC12 cells. The experiments for targeting neurogenesis not only work with thein vitro cultured stem cells but also different animal models for endogenous neurogenesis and iPSCs transplantation. Many critical neurogenic cellular signaling pathways are included in these studies. Importantly, we should emphasize that most of the reported medicinal extracts or pure compounds are obtained from the parent herbs in the catalogs of “Improving Blood Circulation to Resolve Blood Stasis,” “Removing Phlegm Accumulation for Qi Movement in Meridians and Channels” “Removing Internal Heat for Detoxification,” “Dispelling Wind for Regulating Qi-Blood Movement in Meridians and Channels,” and “Tonifying Qi-Blood and Zang-fu Functions” in TCM. Those herbs are generally used for revolving different pathological statues and the different stages of “Wind Stroke” according to classic TCM concepts. Thus, the research progress provides very useful information for bridging the cross talk between TCM and modern conventional medicine in regeneration medicine. In addition, these studies also provide important cues for seeking potential drug candidates for brain repair in different experimental systems.
Nevertheless, it is still premature to draw the conclusion about the scientific basis of those medicinal herbs for poststroke treatments and the related drug discovery. There are many challenging questions remained for future studies: (1) Roles of active compounds and their derivatives for parent medicinal herbs: Indeed, many active compounds or extracts showed their neurogenesis-promoting effects in the literature. It is unclear whether those active compounds are the major compounds contributing to the neurogenic bioactivities of their parent medicinal herbs. Most of the results were only obtained from the in vitro-cultured cell systems or thein vivo animal models by injection of the compounds. Seldom study is conducted to investigate the relationship between the neurogenic effects and the bioavailability of the captioned compounds. For example, tetramethylpyrazine-induced neurogenesis in the postischemic brains, but the bioavailability of this compound was not investigated in those studies., However, evidence from other studies does support that tetramethylpyrazine could pass through the BBB, with the elimination half-life in rat blood and brain of 82.1 and 184.6 min, respectively.,, Ginsenoside Rg1 treatment increased neurogenesis in DG and HIP in both normal and ischemic brains, but the bioavailability was not addressed in those study.,, Interestingly, evidence from another study showed that Ginsenoside Rg1 could be detected in brain extracellular fluid (bECF) and cerebrospinal fluid (CSF), and distributed to the medial prefrontal cortex, HIP, and LV after subcutaneous injection. Such study indicates that Ginsenoside Rg1 could be delivered to the brain to exert its pharmacological effects on neurogenesis. Similarly, Ginsenoside Rb1 could also pass through the BBB, partially via the GLUT1 transporter. α-Asarone passed through BBB after taken into the circulatory system or by traveling from the olfactory epithelium into the brain tissue via the OB. β-Asarone could also distribute into the brain after intragastric administration. Baicalin could penetrate BBB at the dosage of 24 mg/kg with the time to maximum at 30 min in the CSF. Sal B showed direct stimulation effects on neurogenesisin vivo and in vitro, but the bioavailability information was not provided in the same study. Meanwhile, other studies suggest that Sal B had low bioavailability and low penetration through the BBB., Therefore, the neurogenesis effects of Sal B could be possibly indirect. Similarly, AS-IV had limited distribution in the brain tissue, suggesting that it had difficulty in penetrating the BBB. ICA also showed low distribution to the brain tissue. The relationship of their neurogenesis effects and bioavailability needs further investigation. The pharmacokinetics and pharmacodynamics of those compounds in animal models are critical parameters for evaluating the values of drug discovery. The structure and function relationships of the active compounds and their derivatives are also important for further investigations. (2) Molecular targets of active compounds and their derivatives for neurogenesis promotion: many studies investigated the different cellular signal pathways for exploring the underlying mechanisms for neurogenesis in their reports. However, whether those signaling pathways are direct or indirect targets is unknown yet. Many compounds appear to target several molecular targets simultaneously in literature. We recently proposed the one-compound-multitarget concept for the combination prospects of natural compounds with thrombolytic therapy in acute ischemic stroke. Neurogenic effects of the active compounds for promoting neurogenesis should share the same situation. For data interpretation, the pharmacological actions of those compounds could be due to direct interactions, or simply because of the indirect responses of the molecules to the regulation of upstream signaling and/or the synergic effects of the network signaling systems. The changes of the cellular signaling and molecule targets could come from the direct binding of the compounds to the proteins or signaling molecules or only indirectly affected by other factors. (3) Network regulations of medicinal herbs for neurogenesis: Notably, medicinal herbs are generally used as a TCM formula according to the principle of “King-Minister-Assistance-Guider” in the TCM clinical practice. Given that single herb alone already contains 1000 bioactive compounds, these active compounds could yield complex interactions and have synergic effects on modulating adult neurogenesis. In a TCM formula, the active compounds from different medicinal herbal components would yield much more complex interactions and network regulations than the single herb. The development of advanced chemical analytic technology and high throughput gene profile platforms provide a unique opportunity to explore the complex synergic effects of different active compounds in TCM formulas. In recent studies, many TCM formulas already revealed their promoting effects on promoting neurogenesis and recovering neurological deficits in the poststroke study. The progress of regeneration medicine and multiple advanced analytic technologies such as proteomics, metabolomics, and bioinformatics greatly facilitate us to explore the complex and magic world of TCM formulas. With the complex synergic effects and interactions, we will write a separate review article to discuss this important topic in the future.
| Conclusion|| |
The combination of stem cell biology and modern Chinese medicine create a novel opportunity for cross talk of TCM and Western medicine in regeneration medicine, leading novel therapeutic strategies for poststroke treatment.
This study was supported by the grants from Shenzhen Science and Technology Innovation Commission (JCYJ20150402152005623), 2011 State Key Project of National Natural Foundation of China (No. 81630101, SIRI/04/09/2014/2), and National Natural Foundation of China (No. 81703741). AoE/P-705/16 Areas of Excellence Scheme, RGC, Hong Kong SAR.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Feigin VL, Forouzanfar MH, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al.
Global and regional burden of stroke during 1990-2010: Findings from the global burden of disease study 2010. Lancet 2014;383:245-54.
Mendis S. Stroke disability and rehabilitation of stroke: World Health Organization perspective. Int J Stroke 2013;8:3-4.
Liu M, Wu B, Wang WZ, Lee LM, Zhang SH, Kong LZ. Stroke in China: Epidemiology, prevention, and management strategies. Lancet Neurol 2007;6:456-64.
Beal CC. Gender and stroke symptoms: A review of the current literature. J Neurosci Nurs 2010;42:80-7.
Balami JS, Sutherland BA, Buchan AM. Complications associated with recombinant tissue plasminogen activator therapy for acute ischaemic stroke. CNS Neurol Disord Drug Targets 2013;12:155-69.
Zhang L, Zhang ZG, Chopp M. The neurovascular unit and combination treatment strategies for stroke. Trends Pharmacol Sci 2012;33:415-22.
Gross CG. Neurogenesis in the adult brain: Death of a dogma. Nat Rev Neurosci 2000;1:67-73.
Temple S. The development of neural stem cells. Nature 2001;414:112-7.
Alvarez-Buylla A, Garcia-Verdugo JM. Neurogenesis in adult subventricular zone. J Neurosci 2002;22:629-34.
Cameron HA, McKay RD. Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus. J Comp Neurol 2001;435:406-17.
Picard-Riera N, Nait-Oumesmar B, Baron-Van Evercooren A. Endogenous adult neural stem cells: Limits and potential to repair the injured central nervous system. J Neurosci Res 2004;76:223-31.
Plane JM, Liu R, Wang TW, Silverstein FS, Parent JM. Neonatal hypoxic-ischemic injury increases forebrain subventricular zone neurogenesis in the mouse. Neurobiol Dis 2004;16:585-95.
Thored P, Wood J, Arvidsson A, Cammenga J, Kokaia Z, Lindvall O. Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke. Stroke 2007;38:3032-9.
Macas J, Nern C, Plate KH, Momma S. Increased generation of neuronal progenitors after ischemic injury in the aged adult human forebrain. J Neurosci 2006;26:13114-9.
Chen X, Zhou B, Yan T, Wu H, Feng J, Chen H, et al.
Peroxynitrite enhances self-renewal, proliferation and neuronal differentiation of neural stem/progenitor cells through activating HIF-1α and Wnt/β-catenin signaling pathway. Free Radic Biol Med 2018;117:158-67.
Kwak KA, Kwon HB, Lee JW, Park YS. Current perspectives regarding stem cell-based therapy for ischemic stroke. Curr Pharm Des 2018;24:3332-40.
Marei HE, Hasan A, Rizzi R, Althani A, Afifi N, Cenciarelli C, et al.
Potential of stem cell-based therapy for ischemic stroke. Front Neurol 2018;9:34.
Nagpal A, Choy FC, Howell S, Hillier S, Chan F, Hamilton-Bruce MA, et al.
Safety and effectiveness of stem cell therapies in early-phase clinical trials in stroke: A systematic review and meta-analysis. Stem Cell Res Ther 2017;8:191.
Shen J, Chen X. Drug discovery from traditional Chinese medicine for neurogenesis: Implications for stroke and neurodegenerative diseases. Traditional Chinese Medicine: Scientific Basis for Its Use. Cambridge: Royal Society of Chemistry Publishing; 2013. p. 204-37.
Zhang E, Shen J, So KF. Chinese traditional medicine and adult neurogenesis in the hippocampus. J Tradit Complement Med 2014;4:77-81.
] [Full text]
Shen J, Chen X, Chen X, Deng R. Targeting neurogenesis: A promising therapeutic strategy for post-stroke treatment with Chinese herbal medicine. Integr Med Int 2014;1:5-18.
Shu T, Pang M, Rong L, Zhou W, Wang J, Liu C, et al.
Effects of Salvia miltiorrhiza
on neural differentiation of induced pluripotent stem cells. J Ethnopharmacol 2014;153:233-41.
Zhang N, Kang T, Xia Y, Wen Q, Zhang X, Li H, et al.
Effects of salvianolic acid B on survival, self-renewal and neuronal differentiation of bone marrow derived neural stem cells. Eur J Pharmacol 2012;697:32-9.
Shu T, Pang M, Rong L, Liu C, Wang J, Zhou W, et al.
Protective effects and mechanisms of salvianolic acid B against H₂O₂-induced injury in induced pluripotent stem cell-derived neural stem cells. Neurochem Res 2015;40:1133-43.
Zhao Y, Xu P, Hu S, Du L, Xu Z, Zhang H, et al.
Tanshinone II A, a multiple target neuroprotectant, promotes caveolae-dependent neuronal differentiation. Eur J Pharmacol 2015;765:437-46.
Shu T, Liu C, Pang M, He L, Yang B, Fan L, et al.
Salvianolic acid B promotes neural differentiation of induced pluripotent stem cells via PI3K/AKT/GSK3β/β-catenin pathway. Neurosci Lett 2018;671:154-60.
Kong X, Zhong M, Su X, Qin Q, Su H, Wan H, et al.
Tetramethylpyrazine promotes migration of neural precursor cells via activating the phosphatidylinositol 3-kinase pathway. Mol Neurobiol 2016;53:6526-39.
Yan Y, Zhao J, Cao C, Jia Z, Zhou N, Han S, et al.
Tetramethylpyrazine promotes SH-SY5Y cell differentiation into neurons through epigenetic regulation of topoisomerase IIβ. Neuroscience 2014;278:179-93.
Xin J, Zhang J, Yang Y, Deng M, Xie X. Radix Angelica sinensis
that contains the component Z-ligustilide promotes adult neurogenesis to mediate recovery from cognitive impairment. Curr Neurovasc Res 2013;10:304-15.
Si Y, Zhu J, Huang X, Zhu P, Xie C. Effects of Panax notoginseng
saponins on proliferation and differentiation of rat embryonic cortical neural stem cells. J Chin Med Assoc 2016;79:256-63.
He X, Deng FJ, Ge JW, Yan XX, Pan AH, Li ZY. Effects of total saponins of Panax notoginseng
on immature neuroblasts in the adult olfactory bulb following global cerebral ischemia/reperfusion. Neural Regen Res 2015;10:1450-6.
] [Full text]
Zhu J, Mu X, Zeng J, Xu C, Liu J, Zhang M, et al.
Ginsenoside Rg1 prevents cognitive impairment and hippocampus senescence in a rat model of D-galactose-induced aging. PLoS One 2014;9:e101291.
Gao J, Wan F, Tian M, Li Y, Li Y, Li Q, et al.
Effects of ginsenoside-Rg1 on the proliferation and glial-like directed differentiation of embryonic rat cortical neural stem cells in vitro
. Mol Med Rep 2017;16:8875-81.
Ye J, Yao JP, Wang X, Zheng M, Li P, He C, et al.
Neuroprotective effects of ginsenosides on neural progenitor cells against oxidative injury. Mol Med Rep 2016;13:3083-91.
Ni N, Liu Q, Ren H, Wu D, Luo C, Li P, et al.
Ginsenoside Rb1 protects rat neural progenitor cells against oxidative injury. Molecules 2014;19:3012-24.
Wang J, Chen W, Wang Y. A Ginkgo biloba
extract promotes proliferation of endogenous neural stem cells in vascular dementia rats. Neural Regen Res 2013;8:1655-62. [Full text]
Chen Y, Huang X, Chen W, Wang N, Li L. Tenuigenin promotes proliferation and differentiation of hippocampal neural stem cells. Neurochem Res 2012;37:771-7.
Mao J, Huang S, Liu S, Feng XL, Yu M, Liu J, et al.
Aherbal medicine for Alzheimer's disease and its active constituents promote neural progenitor proliferation. Aging Cell 2015;14:784-96.
Pao LH, Lu SW, Sun GG, Chiou SH, Ma KH. Three Chinese herbal medicines promote neuroproliferation in vitro
, and reverse the effects of chronic mild stress on behavior, the HPA axis, and proliferation of hippocampal precursor cell in vivo
. J Ethnopharmacol 2012;144:261-9.
Xu M, Chen X, Gu Y, Peng T, Yang D, Chang RC, et al.
Baicalin can scavenge peroxynitrite and ameliorate endogenous peroxynitrite-mediated neurotoxicity in cerebral ischemia-reperfusion injury. J Ethnopharmacol 2013;150:116-24.
Chen H, Guan B, Chen X, Chen X, Li C, Qiu J, et al.
Baicalin attenuates blood-brain barrier disruption and hemorrhagic transformation and improves neurological outcome in ischemic stroke rats with delayed t-PA treatment: Involvement of ONOO-MMP-9 pathway. Transl Stroke Res 2018;9:515-29.
Li Y, Zhuang P, Shen B, Zhang Y, Shen J. Baicalin promotes neuronal differentiation of neural stem/progenitor cells through modulating p-stat3 and bHLH family protein expression. Brain Res 2012;1429:36-42.
Jia Y, Yang Y, Zhou Y, Song Y, Liu L, Song J, et al.
Differentiation of rat bone marrow stromal cells into neuron induced by baicalin. J Chinese Med 2002;82:1337-41.
Gao C, Du Q, Li W, Deng R, Wang Q, Xu A, et al.
Baicalin modulates APPL2/Glucocorticoid receptor signaling cascade, promotes neurogenesis, and attenuates emotional and olfactory dysfunctions in chronic corticosterone-induced depression. Mol Neurobiol 2018;55:9334-48.
Wang HL, Zhou QH, Xu MB, Zhou XL, Zheng GQ. Astragaloside IV for experimental focal cerebral ischemia: Preclinical evidence and possible mechanisms. Oxid Med Cell Longev 2017;2017:8424326.
Li M, Qu YZ, Zhao ZW, Wu SX, Liu YY, Wei XY, et al.
Astragaloside IV protects against focal cerebral ischemia/reperfusion injury correlating to suppression of neutrophils adhesion-related molecules. Neurochem Int 2012;60:458-65.
Zhu SQ, Qi L, Rui YF, Li RX, He XP, Xie ZP. Astragaloside IV inhibits spontaneous synaptic transmission and synchronized Ca2+ oscillations on hippocampal neurons. Acta Pharmacol Sin 2008;29:57-64.
Qu YZ, Li M, Zhao YL, Zhao ZW, Wei XY, Liu JP, et al.
Astragaloside IV attenuates cerebral ischemia-reperfusion-induced increase in permeability of the blood-brain barrier in rats. Eur J Pharmacol 2009;606:137-41.
Li H, Wang P, Huang F, Jin J, Wu H, Zhang B, et al.
Astragaloside IV protects blood-brain barrier integrity from LPS-induced disruption via activating Nrf2 antioxidant signaling pathway in mice. Toxicol Appl Pharmacol 2018;340:58-66.
Tohda C, Tamura T, Matsuyama S, Komatsu K. Promotion of axonal maturation and prevention of memory loss in mice by extracts of Astragalus mongholicus
. Br J Pharmacol 2006;149:532-41.
Huang F, Lan Y, Qin L, Dong H, Shi H, Wu H, et al.
Astragaloside IV promotes adult neurogenesis in hippocampal dentate gyrus of mouse through CXCL1/CXCR2 signaling. Molecules 2018;23. pii: E2178.
Gao H, Dou L, Shan L, Sun Y, Li W. Proliferation and committed differentiation into dopamine neurons of neural stem cells induced by the active ingredients of Radix astragali
. Neuroreport 2018;29:577-82.
Chen X, Wu H, Chen H, Wang Q, Xie XJ, Shen J. Astragaloside VI promotes neural stem cell proliferation and enhances neurological function recovery in transient cerebral ischemic injury via activating EGFR/MAPK signaling cascades. Molecular Neurobiology 2019;56:3053-67.
Wu B, Chen Y, Huang J, Ning Y, Bian Q, Shan Y, et al.
Icariin improves cognitive deficits and activates quiescent neural stem cells in aging rats. J Ethnopharmacol 2012;142:746-53.
Huang JH, Cai WJ, Zhang XM, Shen ZY. Icariin promotes self-renewal of neural stem cells: An involvement of extracellular regulated kinase signaling pathway. Chin J Integr Med 2014;20:107-15.
Huang S, Mao J, Ding K, Zhou Y, Zeng X, Yang W, et al.
Polysaccharides from Ganoderma lucidum
promote cognitive function and neural progenitor proliferation in mouse model of Alzheimer's disease. Stem Cell Reports 2017;8:84-94.
Moon M, Jeong HU, Choi JG, Jeon SG, Song EJ, Hong SP, et al.
Memory-enhancing effects of Cuscuta japonica
Choisy via enhancement of adult hippocampal neurogenesis in mice. Behav Brain Res 2016;311:173-82.
Yan YH, Li SH, Li HY, Lin Y, Yang JX. Osthole protects bone marrow-derived neural stem cells from oxidative damage through PI3K/Akt-1 pathway. Neurochem Res 2017;42:398-405. doi: 10.1007/s11064-016-2082-y. Epub 2016 Oct 12.
Xiao X, Liu Y, Qi C, Qiu F, Chen X, Zhang J, et al.
Neuroprotection and enhanced neurogenesis by tetramethylpyrazine in adult rat brain after focal ischemia. Neurol Res 2010;32:547-55.
Zhang G, Zhang T, Li N, Wu L, Gu J, Li C, et al.
Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post-ischaemic neuroregeneration and recovery of neurological functions in rats. Br J Pharmacol 2018;175:517-31.
Tsai TH, Liang C. Pharmacokinetics of tetramethylpyrazine in rat blood and brain using microdialysis. Int J Pharm 2001;216:61-6.
Xia H, Cheng Z, Cheng Y, Xu Y. Investigating the passage of tetramethylpyrazine-loaded liposomes across blood-brain barrier modelsin vitro
and ex vivo
. Mater Sci Eng C Mater Biol Appl 2016;69:1010-7.
Meng D, Lu H, Huang S, Wei M, Ding P, Xiao X, et al.
Comparative pharmacokinetics of tetramethylpyrazine phosphate in rat plasma and extracellular fluid of brain after intranasal, intragastric and intravenous administration. Acta Pharm Sin B 2014;4:74-8.
Shen L, Zhang J. Ginsenoside rg1 increases ischemia-induced cell proliferation and survival in the dentate gyrus of adult gerbils. Neurosci Lett 2003;344:1-4.
Shen LH, Zhang JT. Ginsenoside Rg1 promotes proliferation of hippocampal progenitor cells. Neurol Res 2004;26:422-8.
Shen L, Zhang J. NMDA receptor and iNOS are involved in the effects of ginsenoside Rg1 on hippocampal neurogenesis in ischemic gerbils. Neurol Res 2007;29:270-3.
Xue W, Liu Y, Qi WY, Gao Y, Li M, Shi AX, et al.
Pharmacokinetics of ginsenoside Rg1 in rat medial prefrontal cortex, hippocampus, and lateral ventricle after subcutaneous administration. J Asian Nat Prod Res 2016;18:587-95.
Wang YZ, Xu Q, Wu W, Liu Y, Jiang Y, Cai QQ, et al.
Brain transport profiles of ginsenoside rb1 by glucose transporter 1:In vitro
and in vivo
. Front Pharmacol 2018;9:398.
Lu J, Fu T, Qian Y, Zhang Q, Zhu H, Pan L, et al.
Distribution of α-asarone in brain following three different routes of administration in rats. Eur J Pharm Sci 2014;63:63-70.
Wu HB, Fang YQ. Pharmacokinetics of beta-asarone in rats. Yao Xue Xue Bao 2004;39:836-8.
Huang H, Zhang Y, Yang R, Tang X. Determination of baicalin in rat cerebrospinal fluid and blood using microdialysis coupled with ultra-performance liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2008;874:77-83.
Zhuang P, Zhang Y, Cui G, Bian Y, Zhang M, Zhang J, et al.
Direct stimulation of adult neural stem/progenitor cellsin vitro
and neurogenesisin vivo
by salvianolic acid B. PLoS One 2012;7:e35636.
Zhang YJ, Wu L, Zhang QL, Li J, Yin FX, Yuan Y. Pharmacokinetics of phenolic compounds of Danshen extract in rat blood and brain by microdialysis sampling. J Ethnopharmacol 2011;136:129-36.
Grossi C, Guccione C, Isacchi B, Bergonzi MC, Luccarini I, Casamenti F, et al.
Development of blood-brain barrier permeable nanoparticles as potential carriers for salvianolic acid B to CNS. Planta Med 2017;83:382-91.
Zhang WD, Zhang C, Liu RH, Li HL, Zhang JT, Mao C, et al.
Preclinical pharmacokinetics and tissue distribution of a natural cardioprotective agent astragaloside IV in rats and dogs. Life Sci 2006;79:808-15.
Xu S, Yu J, Zhan J, Yang L, Guo L, Xu Y. Pharmacokinetics, tissue distribution, and metabolism study of icariin in rat. Biomed Res Int 2017;2017:4684962.
Chen HS, Qi SH, Shen JG. One-compound-multi-target: Combination prospect of natural compounds with thrombolytic therapy in acute ischemic stroke. Curr Neuropharmacol 2017;15:134-56.