Pharmacological intervention for chronic phase of spinal cord injury.

ABSTRACT: Spinal cord injury is an intractable traumatic injury. The most common hurdles faced during spinal cord injury are failure of axonal regrowth and reconnection to target sites. These also tend to be the most challenging issues in spinal cord injury. As spinal cord injury progresses to the chronic phase, lost motor and sensory functions are not recovered. Several reasons may be attributed to the failure of recovery from chronic spinal cord injury. These include factors that inhibit axonal growth such as activated astrocytes, chondroitin sulfate proteoglycan, myelin-associated proteins, inflammatory microglia, and fibroblasts that accumulate at lesion sites. Skeletal muscle atrophy due to denervation is another chronic and detrimental spinal cord injury-specific condition. Although several intervention strategies based on multiple outlooks have been attempted for treating spinal cord injury, few approaches have been successful. To treat chronic spinal cord injury, neural cells or tissue substitutes may need to be supplied in the cavity area to enable possible axonal growth. Additionally, stimulating axonal growth activity by extrinsic factors is extremely important and essential for maintaining the remaining host neurons and transplanted neurons. This review focuses on pharmacotherapeutic approaches using small compounds and proteins to enable axonal growth in chronic spinal cord injury. This review presents some of these candidates that have shown promising outcomes in basic research (in vivo animal studies) and clinical trials: AA-NgR(310)ecto-Fc (AXER-204), fasudil, phosphatase and tensin homolog protein (PTEN) antagonist peptide 4, chondroitinase ABC, intracellular sigma peptide, (-)-epigallocatechin gallate, matrine, acteoside, pyrvate kinase M2, diosgenin, granulocyte-colony stimulating factor, and fampridine-sustained release. Although the current situation suggests that drug-based therapies to recover function in chronic spinal cord injury are limited, potential candidates have been identified through basic research, and these candidates may be subjects of clinical studies in the future. Moreover, cocktail therapy comprising drugs with varied underlying mechanisms may be effective in treating the refractory status of chronic spinal cord injury.

The roles of natural triterpenoid saponins against Alzheimer's disease.

The aging of the world population and increasing stress levels in life are the major cause of the increased incidence of neurological disorders. Alzheimer's disease (AD) creates a huge burden on the lives and health of individuals and has become a big concern for society. Triterpenoid saponins (TS), representative natural product components, have a wide range of pharmacological bioactivities such as anti-inflammation, antioxidation, antiapoptosis, hormone-like, and gut microbiota regulation. Notably, some natural TS exhibited promising neuroprotective activity that can intervene in AD progress, especially in the early stage. Recently, studies have indicated that TS play a pronounced positive role in the prevention and treatment of AD. This review discusses the recent research on the neuroprotection of TS and proceeds to detail the action mechanisms of TS against AD, hoping to provide a reference for drug development for anti-AD.

Diosgenin restores memory function via SPARC-driven axonal growth from the hippocampus to the PFC in Alzheimer's disease model mice.

Central nervous system axons have minimal capacity to regenerate in adult brains, hindering memory recovery in Alzheimer's disease (AD). Although recent studies have shown that damaged axons sprouted in adult and AD mouse brains, long-distance axonal re-innervation to their targets has not been achieved. We selectively visualized axon-growing neurons in the neural circuit for memory formation, from the hippocampus to the prefrontal cortex, and showed that damaged axons successfully extended to their native projecting area in mouse models of AD (5XFAD) by administration of an axonal regenerative agent, diosgenin. In vivo transcriptome analysis detected the expression profile of axon-growing neurons directly isolated from the hippocampus of 5XFAD mice. Secreted protein acidic and rich in cysteine (SPARC) was the most expressed gene in axon-growing neurons. Neuron-specific overexpression of SPARC via adeno-associated virus serotype 9 delivery in the hippocampus recovered memory deficits and axonal projection to the prefrontal cortex in 5XFAD mice. DREADDs (Designer receptors exclusively activated by designer drugs) analyses revealed that SPARC overexpression-induced axonal growth in the 5XFAD mouse brain directly contributes to memory recovery. Elevated levels of SPARC on axonal membranes interact with extracellular rail-like collagen type I to promote axonal remodeling along their original tracings in primary cultured hippocampal neurons. These findings suggest that SPARC-driven axonal growth in the brain may be a promising therapeutic strategy for AD and other neurodegenerative diseases.

Alkannin Attenuates Amyloid ß Aggregation and Alzheimer's Disease Pathology.

Alzheimer's disease (AD) is a neurodegenerative disease that is accompanied by memory decline and cognitive dysfunction. Aggregated amyloid ß formation and accumulation may be one of the underlying mechanisms of the pathophysiology of AD. Therefore, compounds that can inhibit amyloid ß aggregation may be useful for treatment. Based on this hypothesis, we screened plant compounds used in Kampo medicine for chemical chaperone activity and identified that alkannin had this property. Further analysis indicated that alkannin could inhibit amyloid ß aggregation. Importantly, we also found that alkannin inhibited amyloid ß aggregation after aggregates had already formed. Through the analysis of circular dichroism spectra, alkannin was found to inhibit ß-sheet structure formation, which is an aggregation-prone toxic structure. Furthermore, alkannin attenuated amyloid ß-induced neuronal cell death in PC12 cells, ameliorated amyloid ß aggregation in the AD model of Caenorhabditis elegans (C. elegans), and inhibited chemotaxis observed in AD C. elegans, suggesting that alkannin could potentially inhibit neurodegeneration in vivo. Overall, these results suggest that alkannin may have novel pharmacological properties for inhibiting amyloid ß aggregation and neuronal cell death in AD. SIGNIFICANCE STATEMENT: Aggregated amyloid ß formation and accumulation is one of the underlying mechanisms of the pathophysiology of Alzheimer's disease. We found that alkannin had chemical chaperone activity, which can inhibit ß-sheet structure formation of amyloid ß and its aggregation, neuronal cell death, and Alzheimer's disease phenotype in C. elegans. Overall, alkannin may have novel pharmacological properties for inhibiting amyloid ß aggregation and neuronal cell death in Alzheimer's disease.

Causal Relationships between Daily Physical Activity, Physical Function, and Cognitive Function Ultimately Leading to Happiness.

Frailty is a common age-related condition linked with mobility disorders, long-term care, and death. To prevent frailty, physical activities are considered effective. Several studies have indicated that physical activity can influence mental health as well as body function. Physical activity, cognitive function, and subjective mental health must relate to each other. However, most studies only focus on one-to-one interactions. This observational study aims to clarify the overall relationship and causality between subjective mental health, daily physical activity, and physical and cognitive functions. We recruited 45 people (24 males and 21 females) over 65 years old. Participants visited the university twice and were subjected to activity measurements at home. To examine the causal relationships and related structures between the indicators, structural equation modeling was performed. The results suggest that daily physical activity explains physical function, physical function explains cognitive function, and cognitive function explains subjective mental health, quality of life, and happiness. This study is the first to clarify interactive relationships as an axis that start from daily physical activity to happiness in older adults. Upregulating daily physical activity may improve physical and cognitive functions as well as mental health; this might protect and ameliorate physical, mental, and social frailties.

Axonal Regeneration Mediated by a Novel Axonal Guidance Pair, Galectin-1 and Secernin-1.

Galectin-1 (Gal-1), a member of the Galectin family, is expressed in various tissues and responsible for multiple biological activities. Previous studies reported that extracellular Gal-1 participated in axonal growth and repair, and Gal-1 knockout mice exhibited memory impairment. However, no study has demonstrated the direct contribution of intracellular Gal-1 upregulation in neurons to promoting axonal regeneration in the brain and recovering memory function. In the present study, we found that axonal growth is promoted by overexpression of Gal-1 via adeno-associated virus serotype 9 delivery in primary cultured hippocampal neurons. Moreover, Gal-1 was expressed on the membranes of growth cones in hippocampal neurons and interacted with a novel axonal guidance molecule, Secernin-1, which was secreted from prefrontal cortex (PFC) neurons. Gal-1-overexpression-driven axonal growth was enhanced when recombinant (extracellular) Secernin-1 was treated to the axonal site in a neuron device chamber. Direct binding of extracellular Secernin-1 with Gal-1 was detected through immunoprecipitation and immunocytochemistry, demonstrating that Gal-1 possibly works as an axonal guidance receptor for Secernin-1 in hippocampal neurons. In the PFC, the expression of Gal-1 in axonal shafts and terminals of hippocampal neurons was decreased in the 5XFAD mouse model of Alzheimer's disease (AD). Overexpression of Gal-1 in hippocampal neurons recovered memory deficits and induced axonal regeneration toward the PFC in 5XFAD mice. This study suggests that the enhanced interaction of Secernin-1 and Gal-1 can be harnessed as a therapeutic strategy for long-distance and direction-specific axonal regeneration in AD.

Shati/Nat8l Overexpression Improves Cognitive Decline by Upregulating Neuronal Trophic Factor in Alzheimer's Disease Model Mice.

Alzheimer's disease (AD) is a type of dementia characterized by the deposition of amyloid ß, a causative protein of AD, in the brain. Shati/Nat8l, identified as a psychiatric disease related molecule, is a responsive enzyme of N-acetylaspartate (NAA) synthesis. In the hippocampi of AD patients and model mice, the NAA content and Shati/Nat8l expression were reported to be reduced. Having recently clarified the involvement of Shati/Nat8l in cognitive function, we examined the recovery effect of the hippocampal overexpression of Shati/Nat8l in AD model mice (5XFAD). Shati/Nat8l overexpression suppressed cognitive dysfunction without affecting the Aß burden or number of NeuN-positive neurons. In addition, brain-derived neurotrophic factor mRNA was upregulated by Shati/Nat8l overexpression in 5XFAD mice. These results suggest that Shati/Nat8l overexpression prevents cognitive dysfunction in 5XFAD mice, indicating that Shati/Nat8l could be a therapeutic target for AD.

Memory enhancement effect of saponins from Eleutherococcus senticosus leaves and blood-brain barrier-permeated saponins profiling using a pseudotargeted monitoring strategy.

Dried Eleutherococcus senticosus leaves (ESL), also known as Siberian ginseng tea, are beneficial for human neural disorders. Our previous studies showed that the aqueous extract of ESL enhanced memory in mice, and its saponin fraction (ESL-SAP) exhibited promising neuroprotective activities in vitro; however, the in vivo neurally related effect, bioactive material basis, and possible mechanism of action of ESL-SAP have not been investigated. Here, a series of memory and learning tests were carried out, and the results evidenced a significant enhancement effect of ESL-SAP. Furthermore, an in vivo saponin library-guided pseudotargeted strategy was established to support the rapid monitoring of 26 blood-brain barrier (BBB)-permeated saponins from ESL-SAP-administered rats. A further network pharmacology analysis was conducted on BBB-permeated compounds, which indicated that the in vivo mechanism of ESL-SAP might be effective through multiple targets and pathways, such as the AGE-RAGE signaling pathway and PI3K-Akt signaling pathway, to exert neuroprotective effects. Moreover, the molecular docking experiments demonstrated that key BBB-transferred saponins primarily interacted with targets HRAS, MAPK1, and MAPK8 to produce the neuroprotective effect.

Skeletal muscle atrophy-induced hemopexin accelerates onset of cognitive impairment in Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is an unmet medical need worldwide, and physical inactivity is a risk factor for AD. Performing physical exercise is difficult at old age, and thus, decline in physical movement may be a cause of age-associated lowering of the brain function. This study aimed to elucidate the molecular mechanism and onset of the skeletal muscle atrophy-induced acceleration of AD. METHODS: Pre-symptomatic young 5XFAD or non-transgenic wildtype mice were used. The bilateral hindlimbs were immobilized by placing them in casts for 14 days. Cognitive function was evaluated using the object recognition and spatial memory tests. Further, the hindlimb muscles were isolated for organ culture. Conditioned media (CM) of each muscle was separated by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). Protein expressions in the CM were analysed by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry analysis. The expression levels of candidate proteins were quantified using ELISA. After continuous intracerebroventricular (i.c.v.) infusion of recombinant hemopexin, cognitive function was evaluated. Gene microarray analysis of the hippocampus was performed to investigate the molecules involved in the accelerated memory deficit. Real-time reverse transcription polymerase chain reaction and histological analysis confirmed the expression. RESULTS: Casting for 2 weeks reduced skeletal muscle weight. Object recognition memory in the cast-attached 5XFAD mice (n = 7, training vs. test, P = 0.3390) was impaired than that in age-matched wildtype (n = 7, training vs. test, P = 0.0523) and non-cast 5XFAD mice (n = 7, training vs. test, P = 0.0473). On 2D-PAGE, 88 spots were differentially expressed in muscle CM. The most increased spot in the cast-attached 5XFAD CM was hemopexin. Hemopexin levels in the skeletal muscle (n = 3, P = 0.0064), plasma (n = 3, P = 0.0386), and hippocampus (n = 3, P = 0.0164) were increased in cast-attached 5XFAD mice than those in non-cast 5XFAD mice. Continuous i.c.v. infusion of hemopexin for 2 weeks induced memory deficits in young 5XFAD mice (n = 4, training vs. test, P = 0.6764). Lipocalin-2 (Lcn2) messenger RNA (mRNA), neuroinflammation-associated factor, was increased in the hippocampus in hemopexin-infused 5XFAD mice than in control mice. LCN2 protein in the hippocampus was localized in the neurons, but not glial cells. Lcn2 mRNA levels in the hippocampus were also increased by cast-immobilization of the hindlimbs (n = 6, P = 0.0043). CONCLUSIONS: These findings provide new evidence indicating that skeletal muscle atrophy has an unbeneficial impact on the occurrence of memory impairment in young 5XFAD mice, which is mediated by the muscle secreted hemopexin.

Horse Placental Extract Enhances Neurogenesis in the Presence of Amyloid ß.

Human placental extract and animal-derived placental extracts from pigs and horses host a wide range of biological activities. Several placental products are used as medicines, cosmetics, and healthcare substances worldwide. However, the use of placental extracts for neuronal functioning is currently not established because the number of relevant studies is limited. A few previous reports suggested the neuroprotective effect and dendrite genesis effect of placental extract. However, no studies have reported on neurogenesis in placental extracts. Therefore, we aimed to investigate the effects of horse placental extract on neurogenesis, and we examined the protective effect of the extract on the onset of memory disorder. A horse placental extract, JBP-F-02, was used in this study. JBP-F-02 treatment dose-dependently increased the number of neural stem cells and dendrite length under Aß treatment in primary cultured cortical cells. The oral administration of JBP-F-02 to a 5XFAD mouse model of Alzheimer's disease at a young age significantly prevented the onset of memory dysfunction. This study suggests that the extract has the potential to prevent dementia.

A Novel Heptapeptide, GPPGPAG Transfers to the Brain, and Ameliorates Memory Dysfunction and Dendritic Atrophy in Alzheimer's Disease Model Mice.

We investigated the effects of a heptapeptide, GPPGPAG, on memory improvement and neuritic regeneration in Alzheimer's disease models to evaluate its potency as a new anti-Alzheimer's disease (AD) therapy. The anti-AD effects of GPPGPAG were evaluated in Aß-treated cortical neurons and 5XFAD, a mouse model of AD. Exposure of cortical neurons to Aß25-35 for 3 days resulted in atrophy of axons and dendrites. Treatment with GPPGPAG improved the dendritic atrophy of Aß-treated cortical neurons, but not axonal atrophy. Postsynaptic and presynaptic densities under Aß1-42 exposure were increased by GPPGPAG post treatment. Oral administration of GPPGPAG to 5XFAD mice for 15 days improved significantly object recognition memory and dendritic density. Direct infusion of GPPGPAG into the lateral ventricle of 5XFAD mice for 28 days improved object recognition memory. Following oral administration of GPPGPAG in mice, the undigested heptapeptide was detected in the plasma and cerebral cortex. Analysis of target protein of GPPGPAG in neurons by DARTS method identified 14-3-3ε as a bound protein. The protective effect of GPPGPAG on Aß1-42-induced dendritic atrophy was canceled by knockdown of 14-3-3ε. Taken together, these results suggest that GPPGPAG is orally available, transfers to the brain, and ameliorates memory dysfunction in AD brain, which is possibly mediated by 14-3-3ε-related dendritic restoration.

Effects of Cistanche tubulosa Wight Extract on Locomotive Syndrome: A Placebo-Controlled, Randomized, Double-Blind Study.

In an aging society, preventing dysfunction and restoring function of the locomotive organs are necessary for long-term quality of life. Few interventional studies have investigated supplementation for locomotive syndrome. Additionally, very few interventional clinical studies on locomotive syndrome have been performed as placebo-controlled, randomized, double-blind studies. We previously found that the administration of 30% ethanolic extract of Cistanche tubulosa improved walking ability in a cast-immobilized skeletal muscle atrophy mouse model. Therefore, we conducted a clinical study to evaluate the effects of C. tubulosa (CT) extract on the locomotive syndrome. Twenty-six subjects with pre-symptomatic or mild locomotive syndrome completed all tests and were analyzed in the study. Analyses of muscle mass and physical activity were performed based on the full analysis set. Intake of CT extract for 12 weeks increased step width (two-step test) and gait speed (5 m walking test) in patients over 60 years old compared with those in a placebo control (p = 0.046). In contrast, the skeletal muscle mass of the body trunk and limbs was unchanged following administration of CT extract. Adverse effects were evaluated by blood tests; no obvious adverse events were observed following the intake of CT extract. In conclusion, this placebo-controlled, randomized, double-blind study demonstrated that treatment with CT extract significantly prevented a decline in walking ability without any notable adverse effects in patients with locomotive syndrome.

Recovery from spinal cord injury via M2 microglial polarization induced by Polygalae Radix.

BACKGROUND: Spinal cord injury (SCI) is a refractory neurodegenerative disease caused by inflammation. M1 microglia induce inflammation, whereas M2 suppress inflammation and exhibit neuroprotective effects. Following SCI, M1 cells are more predominant than M2 cells, and hence, increasing the predominance of M2 microglia may improve SCI. PURPOSE: We aimed to evaluate the active constituents of herbal medicine that induce M2 predominance and to investigate their effects using SCI model mice. METHODS: Herbal medicine inducing M2 were screened using cultured microglia. After orally administering the active herbal medicine, Polygalae Radix (PR), to SCI model mice, motor function was evaluated. Compounds in the spinal cord following treatment were assessed using liquid chromatography-mass spectrometry. The effects of compounds detected in the spinal cord were investigated in cultured microglia. RESULTS: PR induced M2 predominance in cultured microglia, improved motor function in SCI model mice, and showed a tendency to increase M2 microglia and protect against axonal degeneration in the inured spinal cord. Sibiricose A5 and 3,6'-disinapoyl sucrose were identified as active constituents in PR. CONCLUSION: PR may be a promising candidate for the treatment of SCI by inducing M2 predominance.

Diosgenin content is a novel criterion to assess memory enhancement effect of yam extracts.

Several studies have suggested that some kind of Dioscorea species (yam) or yam-contained herbal medicines have cognitive enhancement effect. However, it has been unknown what is a crucial factor for cognitive enhancement in each Dioscorea species. In this study, we aimed to investigate whether one of the main and brain-penetrating components in yams, diosgenin, can be a novel criterion to assess memory enhancement effect of yam extracts. Although our previous studies showed that administration of diosgenin or diosgenin-rich yam extract enhanced cognitive function in normal mice and healthy humans, we have never evaluated whether the effect depends on diosgenin content or not. Therefore, we compared memory enhancement effects of low diosgenin-contained general yam water extract with diosgenin-rich yam extract on cognitive function in normal mice. We found that unlike diosgenin-rich yam, administration of general yam water extract did not enhance object recognition memory in normal mice. LC-MS/MS analyses revealed that after administration of general yam, diosgenin concentration in the brain did not reach to the effective dose because of the low diosgenin content in the original yam extract. On the other hand, when diosgenin was artificially added into general yam, the extract showed memory enhancement in normal mice and promoted neurite outgrowth in neurons. Our study suggests that diosgenin is actually an active compound in yams for memory enhancement, and diosgenin content can be a criterion for predicting cognitive enhancement effect of yam extracts.

Recovery of motor function of chronic spinal cord injury by extracellular pyruvate kinase isoform M2 and the underlying mechanism.

In our previous study, we found that pyruvate kinase isoform M2 (PKM2) was secreted from the skeletal muscle and extended axons in the cultured neuron. Indirect evidence suggested that secreted PKM2 might relate to the recovery of motor function in spinal cord injured (SCI) mice. However, in vivo direct evidence has not been obtained, showing that extracellular PKM2 improved axonal density and motor function in SCI mice. In addition, the signal pathway of extracellular PKM2 underlying the increase in axons remained unknown. Therefore, this study aimed to identify a target molecule of extracellular PKM2 in neurons and investigate the critical involvement of extracellular PKM2 in functional recovery in the chronic phase of SCI. Recombinant PKM2 infusion to the lateral ventricle recovered motor function in the chronic phase of SCI mice. The improvement of motor function was associated with axonal increase, at least of raphespinal tracts connecting to the motor neurons directly or indirectly. Target molecules of extracellular PKM2 in neurons were identified as valosin-containing protein (VCP) by the drug affinity responsive target stability method. ATPase activation of VCP mediated the PKM2-induced axonal increase and recovery of motor function in chronic SCI related to the increase in axonal density. It is a novel finding that axonal increase and motor recovery are mediated by extracellular PKM2-VCP-driven ATPase activity.

Trigonelline recovers memory function in Alzheimer's disease model mice: evidence of brain penetration and target molecule.

Trigonelline (TGN; 1-methylpyridin-1-ium-3-carboxylate) is a widely distributed alkaloid derived from plants. Since we previously found a neurite outgrowth effect of TGN, we hypothesised that TGN might help to improve memory deficits. Here, the efficacy of TGN in restoring amyloid ß (Aß)-induced axonal degeneration and in improving memory function was investigated in Alzheimer's disease 5XFAD model mice that overexpress mutated APP and PS1 genes. Exposure of Aß25-35 for 3 days induced atrophy of axons and dendrites. Post treatment of TGN recovered the lengths of axons and dendrites. Following oral administration of TGN in mice, TGN itself was detected in the plasma and cerebral cortex. Oral administration of TGN to 5XFAD mice for 14 days showed significant improvement in object recognition memory (P < 0.001) and object location memory (P < 0.01). TGN administration also normalised neurofilament light levels in the cerebral cortex (P < 0.05), which is an axonal damage-associated biomarker. Analysis of target proteins of TGN in neurons by a drug affinity responsive target stability (DARTS) method identified that creatine kinase B-type (CKB) is a direct binding protein of TGN. Treatment with a CKB inhibitor cancelled the TGN-induced axonal and dendritic growth. In conclusion, we found for the first time that TGN penetrates the brain and may activate CKB, leading to axonal formation. This study shows the potential of TGN as a new drug candidate, and a new target molecule, CKB, in memory recovery signalling.

Natural Medicines and Their Underlying Mechanisms of Prevention and Recovery from Amyloid Β-Induced Axonal Degeneration in Alzheimer's Disease.

In Alzheimer's disease (AD), amyloid ß (Aß) induces axonal degeneration, neuronal network disruption, and memory impairment. Although many candidate drugs to reduce Aß have been clinically investigated, they failed to recover the memory function in AD patients. Reportedly, Aß deposition occurred before the onset of AD. Once neuronal networks were disrupted by Aß, they could hardly be recovered. Therefore, we speculated that only removal of Aß was not enough for AD therapy, and prevention and recovery from neuronal network disruption were also needed. This review describes the challenges related to the condition of axons for AD therapy. We established novel in vitro models of Aß-induced axonal degeneration. Using these models, we found that several traditional medicines and their constituents prevented or helped recover from Aß-induced axonal degeneration. These drugs also prevented or helped recover from memory impairment in in vivo models of AD. One of these drugs ameliorated memory decline in AD patients in a clinical study. These results indicate that prevention and recovery from axonal degeneration are possible strategies for AD therapy.

GRP78-Mediated Signaling Contributes to Axonal Growth Resulting in Motor Function Recovery in Spinal Cord-Injured Mice.

Promoting axonal growth is essential for repairing damaged neuronal connections and motor function in spinal cord injury (SCI). Neuroleukin (NLK) exerts axonal growth activity in vitro and in vivo, but the mechanism remains unclear. This study reveals that the 78-kDa glucose-regulated protein (GRP78) is a NLK neuronal receptor that contributes to recovery from SCI. Binding and immunoprecipitation assays indicated that NLK binds to GRP78. Pretreatment to cultured neurons with a GRP78-neutralizing antibody suppressed NLK-induced axonal growth. Blocking cell surface GRP78 inhibited neuronal NLK-induced Akt activation. Treatment with an Akt inhibitor suppressed NLK-induced axonal growth. Continuous administration of NLK into the lateral ventricle of SCI mice increased axonal density in the injured region and restored motor function, which was not observed when NLK was simultaneously administered with a GRP78-neutralizing antibody. These results indicate that GRP78 regulates the NLK-induced axonal growth activity; NLK-GRP78 signaling promotes motor function recovery in SCI, presenting as a potential therapeutic target.

Combined Treatment with Two Water Extracts of Eleutherococcus senticosus Leaf and Rhizome of Drynaria fortunei Enhances Cognitive Function: A Placebo-Controlled, Randomized, Double-Blind Study in Healthy Adults.

We previously found that the water extract of Eleutherococcus senticosus leaves (ES extract) enhanced cognitive function in normal mice. Our study also revealed that the water extract of rhizomes of Drynaria fortunei (DR extract) enhanced memory function in Alzheimer's disease model mice. In addition, our previous experiments suggested that a combined treatment of ES and DR extracts synergistically improved memory and anti-stress response in mice. Although those two botanical extracts are expected to be beneficial for neuropsychological function, no clinical data has ever been reported. Therefore, we performed a placebo-controlled, randomized, double-blind study to evaluate cognitive enhancement and anti-stress effects by the intake of a combined extract in healthy volunteers. The intake period was 12 weeks. The Japanese version of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) test was used for neurocognitive assessment. The combined treatment of ES and DR extracts significantly increased the figure recall subscore of RBANS (p = 0.045) in an intergroup comparison. Potentiation of language domain ((p = 0.040), semantic fluency (p = 0.021) and figure recall (p = 0.052) was shown by the extracts (in intragroup comparison). In anti-stress response, the anxiety/uncertainly score was improved by the extract in an intragroup comparison (p = 0.022). No adverse effects were observed. The combined treatment of ES and DR extracts appear to safely enhance a part of cognitive function in healthy adults.