CNS Factor is a clinically formulated blend of Euphoria longana, Houttuynia cordata, Dioscorea japonica with Schisandra chinensis (Schisandrin B). The combination of Euphoria longana, Houttuynia cordata and Dioscorea japonica has been researched to exert antidepressant effects and increase Brain-derived neurotrophic factor (BDNF) levels in the brain. Schisandra a well- known adaptogen and cognitive aid, has been included for its antioxidant-neuroprotective, mood balancing and anti-inflammatory effects.*

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor widely expressed in the CNS. It has a neuroprotective effect playing an important role in neuronal survival. In the brain, BDNF is involved in plasticity, formation of new synapses, dendritic branching, and modulation of excitatory and inhibitory neurotransmitter profiles. BDNF is active at all stages of development and is essential for learning and memory. Low levels of serum BDNF have been associated with depression implying an inverse relationship between serum BDNF levels and the severity of depression. Decreased levels of BDNF are also associated with neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, multiple sclerosis and Huntington's disease.*

Methylphenidate increases BDNF in the shorter term but decreases BDNF in adults in the longer term and reduces BDNF in adolescents to the degree that it “reduces the development of pre-frontal lobes”. Note: This is why there is a statistically significant increase in suicidal ideation in the patient’s in their early twenties. CNS Factor is a valid substitute for ADHD in children but needs ongoing testing. Patient also needs ongoing supervision for liver enzymes.*

BDNF Expression and Function

BDNF is a member of the neurotrophin family, which also includes neural growth factor (NGF) and neurotrophins 3 and 4. Bdnf gene expression is strongly regulated by a wide array of endogenous and exogenous stimuli (e.g., stress, physical activity, brain injury, diet).*

BDNF is translated as a pro-neurotrophin (pro-BDNF) that can be cleaved into mature BDNF in the cytoplasm by endo-proteases or in the extracellular matrix by plasmin or matrix metalloproteinases (MMP).[1]*

BDNF has a wide array of functions within the brain and is highly abundant in several brain structures. In the brain, BDNF is involved in plasticity, neuronal survival, formation of new synapses, dendritic branching, and modulation of excitatory and inhibitory neurotransmitter profiles. BDNF is active at all stages of development and aging.*

BDNF is also found in peripheral organs, such as the heart, gut, thymus, and spleen. Around 90% of the BDNF in blood is stored within platelets. Many brain pathologies cause reduction of BDNF protein levels both in the brain and serum of patients.[2]*

Methylphenidate and BDNF

Changes in plasma Brain-derived neurotrophic factor (BDNF) levels induced by methylphenidate in children with Attention deficit-hyperactivity disorder (ADHD).*

It has been suggested that BDNF may play a role in the pathogenesis of ADHD. Our aim is to determine whether methylphenidate can induce changes in plasma BDNF levels of children with ADHD.*

Amiri et al., (2013) assessed levels of plasma BDNF in 28 ADHD patients (age range = 3.5-10 years) before and after 6 weeks treatment with effective dosages of methylphenidate.[3]*

The mean plasma BDNF levels increased after 6 weeks of treatment with methylphenidate. Also, they found an improvement in hyperactivity symptoms with decreasing baseline plasma BDNF levels. They recommend that more studies should be conducted in order to assess the possible roles of plasma BDNF levels in treatment response prediction and prognosis.*

HOWEVER longer term studies indicate that:

Methylphenidate does not restore the reduced serum BDNF levels in ADHD children.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of trophic factors, which is the most abundant neurotrophin in the brain. BDNF exerts its effects by binding to the tropomyosin-related kinase B (TrkB) receptor. It enhances the growth and maintenance of several neuronal systems, serves as a neurotransmitter modulator, and participates in mechanisms of neuronal plasticity, such as long-term potentiation and learning.*

Results do not support the only previous contribution that indicates an increase of BDNF in untreated ADHD children, with positive correlation with the severity of the symptoms of inattention. In addition, we report for the first time “basal” response to treatment with PRMPH, with somewhat surprising results, because as neuronal trophic factor, one might expect an increase in serum in response to methylphenidate, that ameliorates neuropsychological and organic immaturity, proven the last in studies of volumetric magnetic resonance imaging (MRI).[4]*

Juvenile methylphenidate reduces prefrontal cortex plasticity via D3 receptor and BDNF in adulthood.*

Early drug intervention in childhood disorders aims to maximize individual potential in the short- and long-term. Consistently, juvenile exposure to psychostimulants, such as methylphenidate (MPH), reduces risk for substance use in animals and sub-populations of individuals with attention deficit hyperactivity disorder (ADHD). Andersen et al., (2014) investigated the effects of MPH on brain plasticity via dopamine receptor D3 (D3R) and brain-derived neurotrophic factor (BDNF) expression in developing rats.*

Across age strong correlations were evident between Drd3 and Bdnf mRNA levels (r = 0.65) and a negative relationship between Drd3 and exon IIc after MPH treatment (r = −0.73). BDNF protein levels did not differ between Veh- and MPH subjects at baseline, but were significantly lower in MPH-treated and cocaine challenged subjects (30.3 ± 9.7%). Bdnf mRNA was significantly higher in MPH-treated subjects, and reversed upon exposure to cocaine. This effect was blocked by nafadotride. Furthermore, Bdnftotal and Bdnf splice variants I, IIc, III/IV, and IV/VI changed across the transitions between juvenility and late adolescence.*

Conclusions: These data suggest a sensitive window of vulnerability to modulation of BDNF expression around adolescence, and that compared to normal animals, juvenile exposure to MPH permanently reduces prefrontal BDNF transcription and translation upon cocaine exposure in adulthood by a D3R-mediated mechanism.[5]*

CNS Factor Formulation Research

The CNS Factor formulation consisting of Dimocarpus longan, Dioscorea japonica and Houttuynia cordata has been researched for its effects on brain-derived neurotrophic factor (BDNF).*

Several clinical reports have shown depression-induced deregulation of serum BDNF concentration. Depressed patients were characterized by low serum BDNF levels, implying an inverse relationship between serum BDNF levels and the severity of depression.[6] [7] [8] Support for this comes from a number of studies demonstrating that treatment with botanical antidepressants has been shown to increase BDNF levels in serum and plasma. [9] [10] [11] [12]*

It is speculated that lower BDNF levels may be caused by dysregulation of BDNF expression. This was evidenced  with decreased BDNF mRNA and protein levels in post- mortem hippocampus and frontal cortex of suicide victims.[13] Recent reports further support the speculation that antidepressant treatment increased BDNF protein levels in serum and in both prefrontal cortex and hippocampus.[14] [15] In the current study, herbal mixture administration with low and high dose increased the BDNF protein levels in hippocampus and cortex com- pared to the stress group. Herbal mixture might have significantly increased the BDNF transcript levels as well although they were not evaluated in our study.*

Several types of stressors have been known to disrupt BDNF expression. Single (one day) or repeated (7 days) immobilization of rats for 2 hours per day markedly reduced BDNF mRNA levels in the dentate gyrus and hippocampus.[16] This was later confirmed by other investigators who used the same stress paradigm.[17]*

It can be proposed that stress induced changes in BDNF protein level may be involved in other brain regions. The other hypothesis is that immobilization stress duration was too long enough to neutralize the downregulation of BDNF expression. Interestingly, brief immobilization stress can induce BDNF expression as part of a compensatory response to preserve hippocampal homeostasis to cope with new stress.[18]*

This study provides further data that NeuroFactor is able to modulate serum corticosterone level in mice under stress conditions. This effect could be either of peripheral origin through a direct action of herbal mixture on adrenal glands, or of central origin via the hypothalamic-pituitary- adrenal axis. The inverse relationship between memory performance and corticosterone level in stress conditions from the study confirms the past report that chronic stress in has mostly impairing effects on memory .[19]* Moreover, a long-term immobilization stress has been shown to affect spatial memory, which is in accordance with the data of short-term immobilization paradigm.[20]*

In conclusion, the study showed that herbal mixture administration has antidepressant effects. Each herb induced the expression of BDNF, pCREB and pAkt. The administration of herbal mixture significantly increased BDNF protein expression in mouse hippocampus and cortex.* 

Dimocarpus longan research

Memory-enhancing

Dimocarpus longan (DL) also known as Euphoria Longan, has memory enhancing effects and that these effects are mediated by increased BDNF expression via the phosphorylated extracellular signal-regulated kinase (pERK) 1/2, phosphorylated cAMP response element binding protein (pCREB), brain-derived neurotrophic factor (BDNF) pathway and by increased immature neuronal survival.[21]*

Cerebral Ischemia/Reperfusion Injury

Compared with the I/R group, polysaccharides of the DL could obviously reduce the neurological score, the infract volume, the brain water content, MDA content, MPO activity, TNF- and IL-1 level, expression of Bax, and increase SOD, GSH, GSH-Px activity and expression of Bcl-2. The present experiments demonstrated that polysaccharides of the DL significantly reduce the MDA content and increase SOD, GSH and GSH-Px activities.*

This study demonstrated that polysaccharides of the DL significantly reduced myeloperoxidase (MPO) colorimetric  activity (final product of lipid peroxidate) and concentrations of TNF- and IL-1 in the brain tissue, the mechanism may be related to polysaccharides of the DL which can scavenge free radicals effectively in vivo.[22]*

Houttuynia cordata research

Alzheimer’s Disease

The aerial part of Houttuynia cordata (HC) is a traditional herbal medicine for furunculus, disorders of urinary system and fever in East Asia and, recently, it has been shown to have effective anti-inflammatory, antioxidant, anti-virus, and anti-leukemic effects.[23] [24] [25] [26] [27] Additionally, there is a report that H. cordata enhances memory and learning in a mouse model via an antioxidant effect.[28]*

HC had a protective effect against Ab-toxicity in regulating intracellular calcium levels, preventing reactive oxygen species overproduction, and inhibiting mitochondria-mediated apoptosis in rat primary neuronal cells.[29] Taken together, the results reported here indicate that HCW has neuroprotective effects against memory impairment by inhibiting tau hyper-phosphorylation and cholinergic dysfunction.*

Huh et al., (2014) evaluated HC, in vitro and in vivo, and conclude that it has effects on cognitive development in two ways, improving cholinergic dysfunction induced by tau hyperphosphorylation and blocking cholinergic receptors.[30] In addition, HCW has a neuroprotective effect via inhibiting Ca2+- induced apoptosis. Phenolic compounds are well known to have antioxidant, anti-inflammatory, and anti-apoptotic effects, then they have been reported to inhibit neurotoxin-induced damages, resulting neuroprotection.[31] [32]*

Chlorogenic acid and caffeic acid have a neuro- protective effect against methylglyoxal or cryo-injury via anti- apoptotic and anti-inflammatory activities.[33] [34] Also, chlorogenic acid has anti-amnesic effect via inhibition of AChE activity.[35] In addition, quercetin and rutin were also showed protective effect from neuronal damage induced by Ab and ischemia.[36] [37] They assumed that phenolic compounds in HC could partially contribute the effects in the present study. From these results, HC may be an effective treatment for improving the cholinergic system and protecting neurons from toxicity.*

Houttuyniae Herba protects rat primary cortical cells from Aβ(25-35)-induced neurotoxicity via regulation of calcium influx and mitochondria-mediated apoptosis.*

Amyloid beta (Aβ) fibrils are believed to play a major role in the pathogenesis of Alzheimer's disease. Although the mechanisms underlying Aβ toxicity remain largely unknown, Aβ fibrils disrupt calcium homeostasis and generate free radicals, resulting in oxidative stress, mitochondrial dysfunction, and apoptotic cell death. Houttuyniae Herba, the aerial part of Houttuynia cordata Thunb. (Saururaceae), is a commonly used herb in traditional Asian medicine. It has been reported to have various bioactivities, including antioxidant effects. In the present study, Park and Oh (2012) investigated the protective effect of standardised Houttuyniae Herba water extract (HCW) against Aβ(25-35)-induced neurotoxicity and its possible mechanisms in rat primary cortical cells.*

Pretreatment with HCW attenuated the cell damage caused by 8 μM Aβ(25-35) exposure, as evidenced by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, a lactate dehydrogenase assay, and microtubule-associated protein 2 immunostaining. Moreover, HCW inhibited the Aβ(25-35)-induced elevation of the intracellular calcium level, reactive oxygen species overproduction, mitochondrial membrane potential disruption, and caspase 3 activation. These results indicate that HCW protects rat primary cortical neurons against Aβ(25-35)-induced toxicity via the regulation of calcium and the inhibition of mitochondria-mediated apoptosis.[38]*

Anti-Neuroinflammatory Effects

Park et al., (2013) evaluated the anti-neuroinflammatory effects of HC in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells, and its anti-oxidant properties and the extract of HC significantly scavenged DPPH free radicals in a concentration-dependent fashion.[39] The increased levels of NO, iNOS and IL-6 in LPS-stimulated BV-2 microglial cells were also suppressed by HC extract in a concentration-dependent manner.*

HC extract exhibited strong antioxidant properties and inhibited the excessive production of pro-inflammatory mediators, including NO, iNOS and IL-6, in LPS-stimulated BV-2 cells. The antioxidant phenolic compounds present in HC extract might play an important role in ameliorating neuroinflammatory processes in LPS-stimulated BV-2 microglial cells. 35*

These data indicate that a 60% extract of HC has in vitro antioxidant activities, and ingestion thereof may reduce the risk of developing neurodegenerative disorders.*

Cognitive Deficits in Cholinergic Dysfunction Alzheimer’s Disease

Houttuynia cordata (HC) has an effect on cognitive development in two ways, by improving cholinergic dysfunction induced by tau hyperphosphorylation and blocking cholinergic receptors. In addition, HC has a neuroprotective effect via inhibiting Ca2+-induced apoptosis. Phenolic compounds in HC could partially contribute the effects as they are well known to have antioxidant, anti-inflammatory, and anti-apoptotic effects, then they have been reported to inhibit neurotoxin-induced damages, resulting neuroprotection.*

Chlorogenic acid and caffeic acid have a neuro-protective effect against methylglyoxal or cryo-injury via anti-apoptotic and anti-inflammatory activities. Also, chlorogenic acid has anti-amnesic effect via inhibition of AChE activity. In addition, quercetin and rutin were also showed protective effect from neuronal damage induced by Aβ and ischemia.[40]*

Epilepsy

Houttuyniae Herba Attenuates Kainic Acid-Induced Neurotoxicity via Calcium Response Modulation in the Mouse Hippocampus.*

Epilepsy is a complex neurological disorder characterized by the repeated occurrence of electrical activity known as seizures. This activity induces increased intracellular calcium, which ultimately leads to neuronal damage.*

In a rat primary hippocampal culture system, Houttuyniae Herba water extract significantly protected neuronal cells from kainic acid toxicity. In a seizure model where mice received intracerebellar kainic acid injections, Houttuyniae Herba water extract treatment resulted in a lower seizure stage score, ameliorated cognitive impairment, protected neuronal cells against kainic acid-induced toxicity, and suppressed neuronal degeneration in the hippocampus. In addition, Houttuyniae Herba water extract regulated increases in the intracellular calcium level, its related downstream pathways (reactive oxygen species production and mitochondrial dysfunction), and calcium/calmodulin complex kinase type II immunoreactivity in the mouse hippocampus, which resulted from calcium influx stimulation induced by kainic acid.*

These results demonstrate the neuroprotective effects of Houttuyniae Herba water extract through inhibition of calcium generation in a kainic acid-induced epileptic model.[41]*

Dioscorea japonica research

Nerve growth factor (NGF)

Nerve growth factor (NGF) was first discovered by Levi-Montalcini in 1966. NGF has neurotrophic actions that protect cholinergic neurons of the basal forebrain against axotomy-induced neurodegeneration and aged-related atrophy. Exogenous NGF improves impaired function of the cholinergic neuron system, such as neuronal degeneration, and has therapeutic potential for neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease and diabetic polyneuropathy. However, NGF cannot pass through the blood–brain barrier (BBB) and therefore requires neurosurgical approaches for administration. The development of small molecules that induce NGF secretion or mimic NGF activity is therefore desirable.*

In this study two new furostanol saponins (1–2), along with ten known compounds (3–12) isolated from the rhizomes of D. japonica were identified. With regard to bioactivity, compounds 2, 6, 8, 9, and 11 induced NGF secretion in C6 cells at 20 lM. The most potent stimulant of NGF release, coreajaponin B (2), may have a potential for neuroprotection via inducing NGF secretion and may deserve further investigation as a candidate for regulation of neurodegenerative diseases and diabetic polyneuropathy.[42]*

Schisandra (Sch B) Research

Ageing

Mitochondrial decay in ageing: ‘Qi‐invigorating’ schisandrin B as a hormetic agent for mitigating age‐related disease.*

The mitochondrial free radical theory of ageing (MFRTA) proposes a primary role for mitochondrial reactive oxygen species (ROS) in the ageing process. The reductive hot spot hypothesis of mammalian ageing serves as a supplement to the MFRTA by explaining how the relatively few cells that have lost oxidative phosphorylation capacity due to mitochondrial DNA mutations can be toxic to the rest of the body and result in the development of age‐related diseases.*

Schisandrin B (SchB), which can induce both a glutathione anti‐oxidant and a heat shock response via redox‐sensitive signalling pathways, is a hormetic agent potentially useful for increasing the resistance of tissues to oxidative damage. The enhanced cellular/mitochondrial anti‐oxidant status and heat shock response afforded by SchB can preserve the structural and functional integrity of mitochondria, suggesting a potential role for SchB in ameliorating age‐related diseases.[43]*

Alzheimer’s Disease

Glycogen synthase kinase-3β (GSK-3β) is a key enzyme in hyper-phosphorylation of tau proteins and is a promising therapeutic target in Alzheimer’s disease (AD). The stereoisomers of Schisandrin B (Sch B), (+)–1, (–)–1, (+)–2, and (–)–2, were potent GSK-3β inhibitors. These compounds can alleviate the cell injury induced by Aβ, and the cognitive disorders in AD mice, especially (+)-2 and (-)-2. Collectively, the stereoisomers of Sch B, especially (+)–2 and (–)–2, were found to be potential selective ATP-competitive GSK-3β inhibitors, which further affected their anti-AD effects. These promising findings explained the biological target of Sch B in AD, and bring a new understanding in the stereochemistry and bioactivities of Sch B.[44]*

Alzheimer’s disease

Schisandrin B was found to restore cell morphological appearance and viability following Aβ1-42 induced SH- SY5Y cells in a concentration-dependent manner. The inhibitory effect mediated by schisandrin B on AD model cells involved DNA methylation via regulation of DNMT3A and DNMT 1 mRNA expression, sequentially increasing DNMT 3A and DNMT 1 protein expression levels.[45]* 

In another study, results from MTT assay and the Hoechst 33342 staining demonstrate that Aβ25-35 is harmful to PC12 cells, but Schisandrin B can inhibit the damage induced by Aβ25-35 and improve cell viability. Moreover, after treatment with different concentrations of Schisandrin B, cell viability increases and the rate of apoptosis decreases gradually, meaning that Schisandrin B protects PC12 cells from Aβ25-35-induced damage in a dose-dependent manner. Schisandrin B can protect PC12 cells from Aβ25-35-induced injury, and the expression of both VPS35 and APP is decreased. A possible mechanism is that, after addition of Schisandrin B, VPS35 expression decreases, which leads to secondary reductions in sorting protein-related receptor containing LDLR class A repeats (SorLA), its cargo receptor. SorLA is closely linked to the endocytic process of APP hydrolysis to Aβ. Therefore, the degradation of APP is attenuated, inhibiting the production of toxic Aβ. Moreover, as VPS35 decreases, the transport time of APP from the endosome to the trans-Golgi network (TGN) increases, correspondingly reducing the time during which APP protein is associated with its catenase on the cell membrane, and finally inhibiting Aβ formation.[46]*

Insomnia

Huang et al., assessed the sedative and hypnotic activities of the ethanol fraction of Fructus Schisandrae fruit (SY3).[47] In the open field test, SY3 (25, 50 and 100 mg/kg) significantly inhibited the motor activity of mice compared to the normal. Results also showed SY3 potentiated pentobarbital-induced sleep by not only increasing the number of falling asleep and prolonging sleeping time but also reducing sleep latency.*

Furthermore, sleep–wake stages of rats were evaluated by polytrophic recording for 3 h after treatment. The results demonstrated that SY3 at doses of 20, 40 and 80 mg/kg behaved remarkable action on sleep architecture of rats, which contain the increase of total sleeping time, the rate of deep slow wave sleep (SWS) and mean episode duration of deep SWS, and the decrease of the latency of deep SWS. Therefore, these results suggest that the ethanol fraction of Fructus Schisandrae fruit possesses potent sedative and hypnotic activity, which supported its therapeutic use for insomnia.*

Mitochondrial function

The common mechanistic features of most age-related neurodegenerative diseases involve the mitochondrial-derived free radical generation and the existence of a hypometabolic state (i.e., a cellular energy deficit) which results from mitochondrial functional impairment. The enhancement of mitochondrial function (i.e., respiratory activity) by Sch B has been shown to stimulate mitochondrial ATP generation in aging mouse brains.[48] Improvement in respiratory function has been proposed to stimulate the activity of sirtuin, which can activate antiapoptotic, anti-inflammatory, and anti-stress responses, as well as modulate the aggregation of proteins associated with neurodegenerative conditions, thereby preventing or delaying the onset of neurological damage.[49] *[50]*

The neuroprotective effects of Sch B is closely related to its antioxidant activity, in which the antioxidant depletion associated with scopolamine toxicity was ameliorated by Sch B treatment, as indicated by enhancements in GSH levels, GPX, and SOD activities as well as a reduction in malondialdehyde and nitrite levels in brain tissue.[51]*

This study, the ability of Sch B to ameliorate memory deficits was associated with its ability to suppress the activation of NF-κB. The inhibition of NF-κB by Sch B was further demonstrated in this study by the reduction of the downstream activation of p53 and caspase 3. NF-κB has been well established as a common mediator of cDDP-induced cytotoxicity and has been implicated in many other neurodegenerative diseases such as AD, PD, and HD.[52] Therefore, the ability of Sch B to modulate NF-κB, p53, and caspase-3 signaling pathways further strengthens the prospect of its potential use for preventing or ameliorating neurodegenerative disorders.[53]*

Memory impairment in Alzheimer's disease

Sch B attenuated learning and memory impairment of AD mice induced by Aβ1-42. The restoration of glutamate transporter type 1 (GLT-1) and the capacity of glycogen synthase kinase3β (GSK3β) were maintained by Sch B treatment.*

In a study by Chen et al. Sch B showed a protective effect in rats with cerebral ischemia/reperfusion (I/R) injury by strengthening the cerebral mitochondrial antioxidant effect.[54] With the Sch B treatment, the GSH, α-TOC, and Mn-SOD expressions were increased, whereas the MDA-level and Ca2+-induced permeability transition was decreased. In addition, Sch B relieved microglial-mediated inflammatory injury by inhibiting ROS and NADPH oxidase activity. Sch B also modulated acetylcholine (ACh). The ACh level was maintained as normal, while the acetylcholinesterase (AChE) activity was inhibited by Sch B.[55]*

Sch B has been effective at inhibiting neural inflammation during in vivo and in vitro studies. Giridharan reported that Sch B modulated receptors for advanced glycation end products (RAGE), NF-κB, and the mitogen-activated protein kinases (MAPK) signaling pathway. Moreover, an overexpression of the proteins prompting inflammation were inhibited by Sch B. Sch B attenuated cerebral ischemia injury in rats by suppressing the overexpression of inflammatory markers in ischemic hemispheres, and relieved microglial-mediated inflammatory injury by inhibiting the TLR4-dependent MyD88/IKK/NF-κB signaling pathway. Moreover, Sch B showed an inhibitory effect on the LPS-induced inflammatory response by suppressing NF-κB activation, while activating PPAR-γ.[56]*

Neuroinflammatory

Microglial-mediated neuroinflammation is now considered to be central to the pathogenesis of various neurodegenerative processes, including Alzheimer's disease and Parkinson's disease. Sch B exerted significant neuroprotective effects against microglial-mediated inflammatory injury in microglia–neuron co-cultures. In addition, Sch B significantly downregulated pro-inflammatory cytokines, including nitrite oxide (NO), tumor necrosis factor (TNF)-α, prostaglandin E2 (PGE2), interleukin (IL)-1β and IL-6. Additionally, Sch B inhibited the interaction of Toll-like receptor 4 with the Toll adapter proteins MyD88, IRAK-1 and TRAF-6 resulting in an inhibition of the IKK/nuclear transcription factor (NF)-κB inflammatory signaling pathway. Furthermore, Sch B inhibited the production of reactive oxygen species (ROS) and NADPH oxidase activity in microglia. In summary, Sch B may exert neuroprotective activity by attenuating the microglial-mediated neuroinflammatory response by inhibiting the TLR4-dependent MyD88/IKK/NF-κB signaling pathway.[57]*

Neuroprotective

Sch B can promote the depolymerization of Aβ oligomers, increase the cell proliferation rates of SH-SY5 Y induced by Aβ, inhibit apoptosis of SH-SY5 Y after injured by Aβ, it can increase expression of Bcl-XL and reduce expression of Caspase-3, inhibit expression of Aβ1-42 and p-Tau, down-regulated expression of NF-κB/TNF-α signaling pathway.[58]*

Using the elevated plus maze and open field test, Wu et al., (2019) found that forced swimming, an acute stressor, significantly induced anxiety-like behavior that was alleviated by oral Sch B treatment.[59]In addition, the Sch B treatment reduced toxicity, malondialdehyde levels, and production of reactive oxygen species, an important factor for neuron damage.*

Moreover, a higher percentage of intact cells in the amygdala of treated mice, revealed by Nissl staining, further verified the neuroprotective effect of Sch B. Several proteins, such as Nrf2 and its endogenous inhibitor Kelch-like ECH-associated protein 1 (Keap1), were abnormally expressed in mice subjected to forced swimming, but this abnormal expression was significantly reversed by Sch B treatment. The results suggest that Sch B may be a potential therapeutic agent against anxiety associated with oxidative stress. The possible mechanism is neuroprotection through enhanced antioxidant activity.*

Oxidative Stress

Schisandrin B protects neurons from oxidative stress in the central nervous system. Here Wu et al.,  investigated the neuroprotective effect of Sch B against damage caused by acute oxidative stress and attempted to define the possible mechanisms. Using the elevated plus maze and open field test, they found that forced swimming, an acute stressor, significantly induced anxiety-like behavior that was alleviated by oral Sch B treatment.[60]*

In addition, the Sch B treatment reduced toxicity, malondialdehyde levels, and production of reactive oxygen species, an important factor for neuron damage. Antioxidants under the control of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, such as superoxide dismutase and glutathione, were significantly increased by Sch B treatment.*

Their results suggest that Sch B may be a potential therapeutic agent against anxiety associated with oxidative stress. The possible mechanism is neuroprotection through enhanced antioxidant activity.*

Parkinson's disease

MiR-34 family members have been previously shown to play potential functional role in Parkinson's disease (PD) pathogenesis. This study aims to clarify the potential neuroprotective effect of Sch B involving miR-34a function in 6-OHDA-induced PD model.*

Sch B pretreatment ameliorated 6-OHDA-induced changes in vitro, like upregulated miR-34a expression, inhibited Nrf2 pathways and decreased cell survival, and PD feathers in vivo. Moreover, Nrf2 was negatively regulated by miR-34a, while miR-34a overexpression inhibited the neuroprotection of Sch B in both dopaminergic SH-SY5Y cells and PD mice.*

Sch B showed neuroprotective effect in 6-OHDA-induced PD pathogenesis, which could be inhibited by miR-34a, involving the negative regulatory mechanism of miR-34a on Nrf2 pathways.[61]*

Neuroprotective Effect of Schisandra Chinensis on Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonian Syndrome in C57BL/6 Mice.*

Schisandra chinensis  is  a  well-known  botanical  medicine and nutritional supplement that has been shown to have potential effects on neurodegeneration. To investigate the potential neuroprotective effect of S. chinensis fruit extract, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was used to induce behavioural disorders and dopaminergic neuronal damage in mice, and biochemical indicators were examined.*

S. chinensis extract pretreatment (0.5, 1.5, 5 g/kg, p.o.); and S. chinensis extract treatment (0.5, 1.5, 5 g/kg, p.o.). Liquid chromatography coupled to electrochemical detection was used to monitor neurochemicals in the striatum. Tyrosine hydroxylase content was measured by immunohistochemistry, and biochemical antioxidative indicators were used to evaluate the potential neuroprotective effects of S. chinensis fruit extract. The results demonstrated that treatment with*

S. chinensis fruit extract ameliorated MPTP-induced deficits in behaviour, exercise balance, dopamine level, dopaminergic neurons, and tyrosine hydroxylase-positive cells in the striatum of mice. Among the pretreated and treatment groups, a high dose of S. chinensis fruit extract was the most effective treatment. In conclusion, S. chinensis fruit extract is a potential herbal drug candidate for the amelioration and prevention of Parkinson’s disease.[62]*

Spinal cord injury

Notably, Sch B reduced the activation of traumatic injury-associated pathways, including SOD, MDA, NF-κB p65 and TNF-α, in TSCI rats. In addition, Sch B suppressed the TSCI-induced expression of caspase-3 and p-p53 in TSCI rats. These results indicated that Sch B may attenuate the inflammatory response, oxidative stress and apoptosis in TSCI rats by inhibiting the p53 signaling pathway in adult rats.[63]*

Inflammasome‐mediated disorders

Results showed that Sch B can induce a nuclear factor erythroid 2‐related factor 2‐driven thioredoxin expression in primary peritoneal macrophages and cultured RAW264.7 macrophages.*

Sch B suppressed the LPS/ATP‐induced activation of caspase 1 and release of IL‐1β in peritoneal macrophages. Sch B also attenuated the LPS/ATP‐induced ROS production, JNK1/2 activation and LDH release in RAW264.7 macrophages.*

The ability of Sch B to suppress LPS/ATP‐mediated inflammation in vitro was further confirmed by an animal study, in which Sch B treatment (2 mmol/kg p.o.) ameliorated the Inject Alum‐induced peritonitis, as indicated by suppressions of caspase1 activation and plasma IL‐1β level. The ensemble of results suggests that Sch B may offer a promising prospect for preventing the inflammasome‐mediated disorders.[64]*