Part Ⅱ：Research Progress in The Effect Of Traditional Chinese Medicine For Invigoration On Neurotransmitter Related Diseases

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5. The Effects of Traditional Chinese Medicine on Neurotransmitters

5.1. Qi-Tonifying Drugs.

The common representative medicines of Qi-tonifying drugs are Rhodiola Rosea, Acanthopanax senticosus, Radix Ginseng, Licorice, Panax quinquefolius, Astragalus membranaceus, and so on.

The following herbs and active ingredients play antidepressant roles by affecting neurotransmitters.

Rhodiola Rosea is of the genus Rhodiola and is a plant of the Crassulaceae family of succulent leaf plants. After 1.5, 3, and 6 g/kg treatment of Rhodiola Rosea, 5-HT levels in male Sprague-Dawley (SD) rats were observed to be significantly higher than those of the CMUS group, whereas 5-HT levels in the medium and high dosage group were normal. In the low dosage group, however, 5-HT levels were observed to be significantly higher than those of the control group [43].

Acanthopanax senticosus (ASE) is of the genus Eleutherococcus and is a plant of the Araliaceae family of ivy plants. A. senticosus has been widely used in the treatment of mental disorders for many thousands of years. In terms of the FST, ASE at dosages of 500, 1000, and 2000 mg/kg were administered to male Kunming mice at a weight of 18–20 g over seven days, whereas ASE was observed to significantly reduce immobility time compared with the control group. Furthermore, ASE was observed to increase 5-HT levels and also significantly increased DA and NE levels in a dose-dependent manner [44].

Licorice is of the genus Glycyrrhiza and is a plant of the Leguminosae family of flowering plants. It has been reported that an aqueous extract of G. glabra L. showed significant antidepressant-like activity in mouse immobility tests [45]. A previous study found that a flavone compound, liquiritin, isolated from G. uralensis demonstrated an antidepressant effect on chronic stress-depressed rats [46]. In the present study, liquiritin and another flavonoid from G. uralensis, isoliquiritin, were investigated to determine their antidepressant activities. Liquiritin and isoliquiritin are the active ingredients of Licorice. Liquiritin and isoliquiritin at dosages of 10, 20, and 40 mg/kg were observed to significantly decrease the immobility time in mice during FST and TST. At medium concentrations, liquiritin and isoliquiritin were both found to increase 5-HT and NE levels in the hippocampus, hypothalamus, and cortex in mice in both the FST and TST. However, liquiritin and isoliquiritin also significantly decreased the ratio of 5-HIAA/5-HT in all measured brain regions in both the FST and TST [47].

Ginseng is of the genus Panax and is a plant of the Araliaceae family of ivy plants. Ginseng has been used for mood adjustment in traditional Chinese medicine for thousands of years. The previous study has shown that total ginsenosides, the major pharmacologically functional ingredients of ginseng, possess antidepressant activity [48]. In the present study, they hypothesized that an intestinal metabolite of ginseng, 20(S)-protopanaxadiol (code name S111), as a post metabolism compound (PMC) of ingested ginsenosides, may be responsible for the antidepressant activity of ginseng. Male Swiss mice weighing 18–22 g were administered S111 at dosages of 3.75, 7.5, and 15 mg/kg over a treatment period of 10 days. The immobility time of the mice was observed to decrease in both the FST and TST. Furthermore, male SD mice at a weight of 200–250 g that underwent an olfactory bulbectomy (OB) were observed to have lower levels of NE and 5-HT than those mice who underwent an FST and TST. After treatment with S111 at 13.33 mg/kg and 6.67 mg/kg daily for 14 days, the levels of NE and 5-HT were significantly higher than the OB model group [49].

The following herbs and active ingredients may delay the development of PD by affecting the neurotransmitter.

Acanthopanax senticosus is of the genus Eleutherococcus and is a plant of the Araliaceae family of ivy plants. The extract of Acanthopanax senticosus was observed to have a neuroprotective effect against MPTP-induced PD model mice. MPTP can selectively damage neurons in the nigrostriatal dopaminergic pathway and cause PD in humans, nonhuman primates, and mice; thus, mice have become widely accepted as a model for PD [50, 51]. After 20 days of treatment, the DA level of the striatum in the low dose group (45.5 mg/kg) was observed to significantly increase [52].

Panax quinquefolius is the genus of Panax and is a plant of the family Araliaceae of ivy plants. Pseudoginsenoside F11 is a unique component and main monomer in Panax quinquefolius [53]. It has been shown to have many beneficial effects in treating disorders of 6-OHDA-lesioned rats. After treatment with PF11 at dosages of 3, 6, and 12 mg/kg, the level of striatal extracellular DA was observed to significantly increase in a dose-dependent manner compared with 6-OHDA-lesioned PD model rats. At a high dosage, extracellular DA was observed to recover to normal levels. Furthermore, a noticeable restoration of TH was observed in the herb-treated group in a dose-dependent manner [54]

Astragalus membranaceus is of the genus Astragalus and is a plant of the Leguminosae family of flowering plants. A. membranaceus is a medicinal plant traditionally used in Chinese medicine for several conditions, including inflammatory and neural diseases. Astragalus polysaccharides can reduce the adverse effects of levodopa and are used in the treatment of PD [55]. Astragalus at dosages of 1, 2, or 4 mg/ml is capable of alleviating 6-OHDA-mediated dopaminergic neurodegeneration in BZ555 nematodes. AchE is an indirect indicator of cholinergic system function and provides a helpful strategy for alleviating the behavioral deficit in PD progression. After being exposed to 6-OHDA, AchE activity was observed to decrease in BZ555 nematodes. This decreased AchE activity was observed to be significantly elevated when treated with 2 mg/ml of astragalin, indicating that Astragalus can regulate AchE activity in BZ555 nematodes [56]

The following herbs and active ingredients may improve sleep disorders by affecting neurotransmitters.

Licorice is of the genus Glycyrrhiza and is a plant of the Leguminosae family of flowering plants. Glycyrrhiza glabra (GGE) is the root of Glycyrrhiza and is a frequently used natural medicine described as “the grandfather of herbs”. GGE was observed to decrease sleep latency and increase sleep duration in a dose-dependent manner (50, 100, 250, and 500 mg/kg). Its hypnotic effect was observed to show a statistically significant difference at concentrations of 250 and 500 mg/kg compared with the pentobarbital-induced model group. The hypnotic effect observed in this study suggests that GGE has the potential to exert positive allosteric modulation of GABAA-BZD receptors. The specific GABAABZD receptor antagonist flumazenil (FLU) was observed to significantly inhibit the hypnotic effects of GGE at a dosage of 500 mg/kg. This indicates that GGE induces sleep via the GABAergic system and can act as a positive allosteric modulator on GABAA-BZD receptors to activate glabrous compounds (50 mg/kg) [57].

Eleutherococcus senticosus is of the genus Eleutherococcus and is a plant of the Araliaceae family of ivy plants. Eleutheroside E (EE) is a principal component of Eleutherococcus senticosus. The world health organization (WHO) prescribes anthocyanin E as one of the indicators of Acanthopanax quality control [58]. In addition, In China Pharmacopoeia 2010, the content of anthocyanin E in the Acanthopanax extract was determined [59]. Treatment with EE at dosages of 10 and 50 mg/kg was observed to improve behavioral tests of sleep-deprived model mice, such as passive avoidance task locomotor activity and Y-maze testing. Furthermore, after 72-hour sleep deprivation and EE treatment at a dosage of 50 mg/kg, a significant increase in 5-HT concentration was observed. However, the EE (50 mg/kg) treatment group significantly decreased DA concentrations after sleep deprivation when compared to the control group [60]

5.2. Blood-Tonifying Drugs. The most common representative medicines of blood-tonifying drugs are peony, Fallopia multiflora, and so on.

The following active ingredients play an antidepressant role by affecting neurotransmitters.

Peony is of the genus Paeonia lactifora and is a plant of the Ranunculaceae family of flowering plants. The previous studies found that the total glycoside fraction of peony exerted significant antidepressant-like effects in multiple animal models of depression [61, 62]. Paeoniflorin, the main active component in total glycosides of peony, has been extensively studied as an antioxidant, a cognitive enhancer or learning impairment-attenuating agent, and a neuroprotective agent related to depression. It has been observed to increase the sucrose consumption of CMUS-model rats. Compared with CUS rats, Paeoniforin-H (60 mg/kg) can elevate levels of NA, DA, 5-HT, and 5-HIAA in such a way as to decrease the 5-HIAA/5-HT ratio in the central nervous system of CUSmodel rats [63]

The following active ingredients may delay the development of PD by affecting the neurotransmitters.

As mentioned, Peoniforin (PF) is a major bioactive ingredient in the roots of Radix Paeonia Alba. PF has low toxicity and has been demonstrated to have neuroprotective effects. After treatment with PF at dosages of 7.5, 15, and 30 mg/kg, the level of DA and HVA in the striatum were significantly higher than that of the MPTP-treated group, whereas the ratio of HVA/DA was lower than that of the model group. Dopaminergic transporter (DAT) plays a significant role in mediating the return of striatal dopamine. PF at dosages of 7.5, 15, and 30 mg/kg was observed to attenuate the decrease of DAT and TH in the striatum and the substantia nigra [64].

Fallopia multiflora is of the genus Fallopia and is a plant of the Polygonaceae family of knotweed plants. 2,3,5,4?- tetrahydroxystilbene-2-O-?-D-glucoside (TSG) is an active component extracted from this traditional Chinese herb. 2,3,5,4? -Tetrahydroxystilbene-2-O-?-D-glucoside (TSG) was isolated from Fallopia multiflora, a plant that is traditionally used as an antiageing drug. TSG at dosages of 20 and 40 mg/kg was observed to significantly increase the level of DA, DOPAC, and HVA in the striatum. TSG at dosages of 20 and 40 mg/kg was also observed to attenuate the loss of THpositive cells induced by MPTP in a dose-dependent manner. A higher dosage was more effective than a lower dosage [65].

5.3. Yin-Tonifying Drugs. The most common representative medicines of Yin-tonifying drugs are Eclipta, Glossy privet fruit, Lilium brownii, Rhizoma anemarrhenae, and so on.

The following active ingredients may delay the development of AD by affecting the neurotransmitters.

Eclipta compositae is of the genus Eclipta and is a plant of the family Compositae of sunflower plants. A model of Alzheimer’s disease was established with subcutaneous injections of D-galactose and microinjection A? 25–35 on the bilateral hippocampus of male and female SD rats. Eclipta alba was observed to improve the learning and memory function of rats in the AD model. Compared with the AD model group, however, the incubation period was observed to be prolonged in the step-through test, with error times significantly decreased in the high dosage group (24 g/kg). Furthermore, Eclipta alba extract at a dose of 24 g/kg was observed to significantly enhance the contents of NE, DA, and 5-HT in the hippocampus of AD model rats. In addition, a high dosage was also observed to increase ChAT activity and significantly decline AchE [66]

The following Yin-nourishing prescription improves symptoms of perimenopausal syndrome by affecting neurotransmitters.

ErzhiBaihe concentrated cream is used for the treatment of early-stage of menopause and consists of tonic herbs, including Glossy privet fruit, Eclipta, Lilium brownii, and Rhizoma anemarrhenae. Various concentrations of ErzhiBaihe cream (1.92, 0.96, 0.48 g/kg) were administered to the model rats and the level of NE, DA, and 5-HT in their hypothalamus was observed to decrease. The difference between the high dose group and the model group was also observed to be statistically significant. These results demonstrate that the Erzhi Recipe could rectify hypothalamic neurotransmitter disorders and efficiently regulate the endocrine disturbance of model rats [39].

5.4. Yang-Tonifying Drugs. The most common representative medicines of Yang-tonifying drugs are Psoralea corylifolia, Morinda officinal, Cistanche tubulosa, Fructus Alpinia oxyphylla, Fructus Alpinia oxyphylla, and so on

The following active ingredients play an antidepressant role by affecting neurotransmitters.

Psoralea corylifolia is of the genus Psoralea and is a plant of the Leguminosae family of flowering plants. The previous studies demonstrated that the total furocoumarins extracts of P. corylifolia had potent antidepressant properties by employing the forced swimming test (FST) [67]. Psoralen is a main furocoumarin isolated from the seeds of Psoralea corylifolia. Male mice of the ICR strain at a weight of 23–25 g were administered psoralen at dosages of 10, 20, and 40 mg/kg over a 14-day treatment period. At the end of treatment, immobility time was observed to significantly increase in the FST, with 20 and 40 mg/kg dosages significantly increasing swimming time. While psoralen treatment was not observed to affect the 5-HIAA/5-HT ratio, psoralen at a dosage of 20 mg/kg significantly increased 5-HT levels in the hippocampus and frontal cortex of the mice [68].

The following herbs and active ingredients may delay the development of AD by affecting the neurotransmitter.

Morinda officinal is of the genus Morinda and is a plant of the Rubiaceae family of flowering plants. Morinda Officinalis mainly contains compounds and inorganic elements such as sugar, quinone, amino acids, lipids, and organic acids [69]. Among them, the content of oligosaccharides is up to 50%, the composition is complex, and the pharmacological action is obvious. Bajijiasu is an oligosaccharide monomer isolated from Morinda Officinalis, and it has the activity of invigorating the kidney and brain, which can obviously improve the behavior of vascular dementia rats [70]. In the Alzheimer’s disease (AD) model, male SD rats were injected with A? 25–35 into the bilateral CA1 region of the hippocampus. Bajijiasu at dosages of 8, 24, and 48 mg/kg was observed to ameliorate A?-induced learning and memory dysfunction compared with the AD model group. The escape latency of each BJ-treated group was significantly shorter in the Morris water maze. After Bajijiasu was administered at different concentrations, the levels of Ach, 5-HT, and DA were found to significantly increase while AchE decreased [71].

Cistanche tubulosa (CT) is of the genus Cistanche and is a plant of the family Orobanchaceae of parasitic plants. All doses of Cistanche Tubulosa (100, 200 mg/kg) extract significantly increased the time spent in the platform-quadrant of the Morris water maze and increased the step-through latency of the inhibitory avoidance task compared to A? 1–42-infused male SD rats. A? 1–42 was observed to decrease the expression of DA and Ach in the hippocampus, which could be improved by the aqueous extracts of Cistanche Tubulosa at a dosage of 200 mg/kg. Furthermore, Cistanche Tubulosa extract (200 mg/kg) was observed to reduce ACHE and MAO-A cortical activity in the model group after 15 days of treatment [72].

The following herbs and active ingredients may delay the development of PD by affecting neurotransmitters.

Fructus Alpinia oxyphylla (AOE) is of the genus Alpinia and is a ripe fruit of the Zingiberaceae family of flowering plants. AOE was observed to increase locomotor activity in 6-OHDA-treated Zebrafish. Furthermore, AOE at dosages of 6 and 12 ug/ml was observed to significantly attenuate the loss of the DA Neuron of 6-OHDA induced in Zebrafish. Furthermore, the DA neuron almost completely recovered by giving high doses of AOE [73].

Psoralea corylifolia is of the genus Psoralea and is a plant of the Leguminosae family of flowering plants. Te monoterpenoids are dominant components in the “volatile oils” of plant species and △3,2-hydroxy bakuchiol (BU) is an important monoterpene phenol compound in Psoralea corylifolia [74]. BU at dosages of 5.44, 16.32, or 48.96 mg/kg was observed to significantly inhibit the uptake of DA in striatal synaptosomes and NE in the hippocampal synaptosomes of male SD rats. BU at dosages of 4, 20, or 100 mg/kg was also observed to significantly inhibit the decrease of TH-positive neuronal populations in the substantia nigra (SN) of MPTP model male C57BL/6J mice [75].

The following active ingredients may improve sleep disorders by affecting neurotransmitter

Fructus Alpinia oxyphylla is of the genus Alpinia and is a ripe fruit of the Zingiberaceae family of flowering plants. Glutamic acid (Glu) is the main excitatory neurotransmitter in the central nervous system (CNS). An increase in the release of Glu can induce excitatory neurotoxicity. The ratio of GABA/Glu plays a critical role in the balance of excitation and inhibition in neurons. Compared with the control group, the levels of Glu amino acid neurotransmitters were observed to increase, whereas GABA was significantly decreased in the cortex and hypothalamus during rapid eye movement (REM) sleep deprivation. However, the group of volatile oils extracted from Alpinia oxyphylla Fructus (VOA) (9, 27 g/kg) reversed the increase in Glu and decreased GABA compared to the model group [76].

5.5. Tonify Deficiency Prescriptions. Te tonify deficiency prescriptions contain Qi-tonifying, Blood-tonifying, Yin tonifying, and Yang-tonifying drugs which are compatible with each other.

The following prescription may delay the development of PD by affecting the neurotransmitters.

Jia-Jian-Di-Huang-Yin-Zi (JJDHYZ) decoction is a classical prescription of traditional Chinese medicine and contains Radix Paeonia Alba, Angelica Sinensis, Radix Rehmanniae, Morinda Officinalis, and Cistanche. JJDHYZ been used in the treatment of long-term neurological disorders. JJDHYZ at a high concentration of 34 g/kg was observed to improve the variation tendency in behavioral pole tests. Furthermore, the injection of MPTP was also observed to demonstrate neurotoxic effects and induce a reduction of dopamine (DA), homovanillic (HVA), and dihydroxyphenylacetic (DOPAC) acids compared with the control group. JJDHYZ at a concentration of 34 g/kg significantly rescued the depletion of DA, DOPAC, and HVA in comparison with the MPTP group [77].

The following prescriptions improve symptoms of perimenopausal syndrome by affecting neurotransmitters.

A herbal recipe derived from Danggui Buxue Decoction consists of Radix astragali, Radix Angelica Sinensis, and Folium Epimedii (RRF), with a ratio of 5 : 1: 5. Te three are Yang-tonifying, Blood-enriching, and Qi-supplementing drugs, respectively. Medium concentrations (282 mg/kg/d) of RRF were observed to significantly inhibit increased hypothalamic NE in rats after they were ovariectomized, whereas high concentrations (564 mg/kg/d) of RRF were observed to significantly reduce the increased hypothalamic DA level in model rats. Finally, high and low concentrations (564 and 141 mg/kg/d) of RRF significantly reduced the increased hypothalamic 5-HT level in the model rats. However, levels of 5-HIAA and the 5-HT metabolite remained unaffected by different concentrations of RRF [40].

Bushen Liaogeng Extract (BLE) is effective in the clinical treatment of perimenopausal syndrome and is prepared from several deficiency-tonifying Chinese herbs, including Radix Rehmanniae Praeparata, Cistanche deserticola, Cynomorium songaricum, and Codonopsis pilosula. Compared with the model group, hypothalamic DA, NE, 5-HT, and 5-HIAA levels in mice from the low, medium, and high dose BLE groups (4.5, 9, and 18 g/kg) were significantly decreased. Therefore, this suggests that BLE can regulate the level of monoamine neurotransmitters in the hypothalamus of ovariectomized mice by restoring its normal status and improving disordered autonomic nervous function during menopause [41].

6. Summary and Future Prospects

The neurotransmitter-related diseases such as depression, Alzheimer’s disease, Parkinson’s disease, sleep disorders, and perimenopausal syndrome are complicated disorders and their pathogenesis remains unclear. These diseases are closely correlated with the dysregulation of central neurotransmitters. At present, there exist no clinically effective medicines available for the treatment of these diseases given their obvious side effects. The theory of traditional Chinese medicine believes that the pathogenesis of such diseases is complicated, involving the Yin-Yang and the Qi-blood of five internal organs. Previous studies have demonstrated that tonic Chinese medicine can improve the symptoms of disease and prolong the development of diseases by supplementing Qi, enriching blood, nourishing Yin, and strengthening Yang. An increasing amount of studies have documented that tonic Chinese medicine plays a therapeutic role and can regulate the secretion of central nervous system neurotransmitters, such as 5-HT, DA, and NE by multicomponent, multichannel, and multitarget therapy. In the future, the exact target, location, and mechanism of the effective ingredient and function of tonic Chinese medicine should be investigated.

Conflicts of Interest

All the authors declare that they do not have any conflicts of interest.

Acknowledgments

This work was supported by the National Natural Science Foundation of China (no. 81373789).

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