Hyperoside Attenuate Inflammation in HT22 Cells via Upregulating SIRT1 to Activities Wnt/ß-Catenin and Sonic Hedgehog Pathways.

Neuroinflammation plays important roles in the pathogenesis and progression of altered neurodevelopment, sensorineural hearing loss, and certain neurodegenerative diseases. Hyperoside (quercetin-3-O-ß-D-galactoside) is an active compound isolated from Hypericum plants. In this study, we investigate the protective effect of hyperoside on neuroinflammation and its possible molecular mechanism. Lipopolysaccharide (LPS) and hyperoside were used to treat HT22 cells. The cell viability was measured by MTT assay. The cell apoptosis rate was measured by flow cytometry assay. The mRNA expression levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α) were determined by quantitative reverse transcription polymerase chain reaction. The levels of oxidative stress indices superoxide dismutase (SOD), reactive oxygen species (ROS), catalase (CAT), glutathione (GSH), and malondialdehyde (MDA) were measured by the kits. The expression of neurotrophic factor and the relationship among hyperoside, silent mating type information regulation 2 homolog-1 (SIRT1) and Wnt/ß-catenin, and sonic hedgehog was examined by western blotting. In the LPS-induced HT22 cells, hyperoside promotes cell survival; alleviates the level of IL-1ß, IL-6, IL-8, TNF-α, ROS, MDA, Bax, and caspase-3; and increases the expression of CAT, SOD, GSH, Bcl-2, BDNF, TrkB, and NGF. In addition, hyperoside upregulated the expression of SIRT1. Further mechanistic investigation showed that hyperoside alleviated LPS-induced inflammation, oxidative stress, and apoptosis by upregulating SIRT1 to activate Wnt/ß-catenin and sonic hedgehog pathways. Taken together, our data suggested that hyperoside acts as a protector in neuroinflammation.

[Effects of vertical water immersion on the nervous system: a systematic review]. / Efectos de la inmersion vertical en el agua sobre el sistema nervioso: revision sistematica.

INTRODUCTION: Vertical immersion induces a variety of physiological responses in different body systems, depending on the properties of fluid mechanics, which are the basis that underpins aquatic therapy programs in different pathologies. AIM: To perform a systematic review to analyze and describe the effects that vertical immersion produces on the nervous system in healthy subjects. SUBJECTS AND METHODS: A systematic search of the existing literature was conducted in the databases BRAIN, PubMed, PEDro and Web of Science. Quality was methodologically assessed using the CASPe guideline and the level of evidence was categorized using the Oxford scale. A total of 12 articles were included, with a score range of 7-10 according to CASPe, levels of evidence 1b-2b and grade of recommendation B. RESULTS: All studies showed positive results to the different forms of exposure of vertical immersion in water and the summation of the stimuli used; no adverse effects were reported in any case. CONCLUSIONS: The vertical immersion in the water generates positive effects on cerebral blood flows, cortical activation, executive functions and the production of neurotrophins in healthy subjects.

TITLE: Efectos de la inmersion vertical en el agua sobre el sistema nervioso: revision sistematica.Introduccion. La inmersion vertical induce una variedad de respuestas fisiologicas en diferentes sistemas corporales, dependiendo de las propiedades de la mecanica de fluidos, las cuales son la base que sustenta los programas de terapia acuatica en diferentes patologias. Objetivo. Realizar una revision sistematica para analizar y describir los efectos que la inmersion vertical produce en el sistema nervioso en sujetos sanos. Sujetos y metodos. Se llevo a cabo una busqueda sistematica de la bibliografia existente en las bases de datos BRAIN, PubMed, PEDro y Web of Science. Se evaluo metodologicamente la calidad mediante la guia CASPe y el nivel de evidencia se categorizo mediante la escala Oxford. Se incluyo un total de 12 articulos, con un rango de puntuacion de 7-10 segun CASPe, niveles de evidencia 1b-2b y grado de recomendacion B. Resultados. Todos los estudios mostraron resultados positivos a las diferentes formas de exposicion de la inmersion vertical en el agua y a la suma de estimulos empleados, sin referir efectos adversos en ningun caso. Conclusiones. La inmersion vertical en el agua genera efectos positivos sobre los flujos circulatorios cerebrales, la activacion cortical, las funciones ejecutivas y la produccion de neurotrofinas en sujetos sanos.

Dose-Dependent Differential Effect of Neurotrophic Factors on In Vitro and In Vivo Regeneration of Motor and Sensory Neurons.

Although peripheral axons can regenerate after nerve transection and repair, functional recovery is usually poor due to inaccurate reinnervation. Neurotrophic factors promote directional guidance to regenerating axons and their selective application may help to improve functional recovery. Hence, we have characterized in organotypic cultures of spinal cord and dorsal root ganglia the effect of GDNF, FGF-2, NGF, NT-3, and BDNF at different concentrations on motor and sensory neurite outgrowth. In vitro results show that GDNF and FGF-2 enhanced both motor and sensory neurite outgrowth, NGF and NT-3 were the most selective to enhance sensory neurite outgrowth, and high doses of BDNF selectively enhanced motor neurite outgrowth. Then, NGF, NT-3, and BDNF (as the most selective factors) were delivered in a collagen matrix within a silicone tube to repair the severed sciatic nerve of rats. Quantification of Fluorogold retrolabeled neurons showed that NGF and NT-3 did not show preferential effect on sensory regeneration whereas BDNF preferentially promoted motor axons regeneration. Therefore, the selective effects of NGF and NT-3 shown in vitro are lost when they are applied in vivo, but a high dose of BDNF is able to selectively enhance motor neuron regeneration both in vitro and in vivo.

Molecular Mechanisms Responsible for Neuron-Derived Conditioned Medium (NCM)-Mediated Protection of Ischemic Brain.

The protective value of neuron-derived conditioned medium (NCM) in cerebral ischemia and the underlying mechanism(s) responsible for NCM-mediated brain protection against cerebral ischemia were investigated in the study. NCM was first collected from the neuronal culture growing under the in vitro ischemic condition (glucose-, oxygen- and serum-deprivation or GOSD) for 2, 4 or 6 h. Through the focal cerebral ischemia (bilateral CCAO/unilateral MCAO) animal model, we discovered that ischemia/reperfusion (I/R)-induced brain infarction was significantly reduced by NCM, given directly into the cistern magna at the end of 90 min of CCAO/MCAO. Immunoblocking and chemical blocking strategies were applied in the in vitro ischemic studies to show that NCM supplement could protect microglia, astrocytes and neurons from GOSD-induced cell death, in a growth factor (TGFß1, NT-3 and GDNF) and p-ERK dependent manner. Brain injection with TGFß1, NT3, GDNF and ERK agonist (DADS) alone or in combination, therefore also significantly decreased the infarct volume of ischemic brain. Moreover, NCM could inhibit ROS but stimulate IL-1ß release from GOSD-treated microglia and limit the infiltration of IL-ß-positive microglia into the core area of ischemic brain, revealing the anti-oxidant and anti-inflammatory activities of NCM. In overall, NCM-mediated brain protection against cerebral ischemia has been demonstrated for the first time in S.D. rats, due to its anti-apoptotic, anti-oxidant and potentially anti-glutamate activities (NCM-induced IL-1ß can inhibit the glutamate-mediated neurotoxicity) and restriction upon the infiltration of inflammatory microglia into the core area of ischemic brain. The therapeutic potentials of NCM, TGFß1, GDNF, NT-3 and DADS in the control of cerebral ischemia in human therefore have been suggested and require further investigation.

Duality of Antidepressants and Neuroprotectants.

The co-morbidity of neuropsychiatric disorders, particularly major depressive disorder (MDD) with neurodegenerative diseases, in particular Parkinson's disease (PD) is now well recognized. Indeed, it is suggested that depressive disorders, especially in late life, may be an indication of latent neurodegeneration. Thus, it is not unreasonable to expect that deterrents of MDD may also deter the onset and/or progression of the neurodegenerative diseases including PD. In this review, examples of neuroprotective efficacy of established as well as prospective antidepressants are provided. Conversely, mood-regulating effects of some neuroprotective drugs are also presented. Thus, in addition to currently used antidepressants, ketamine, nicotine, curcumin, and resveratrol are discussed for their dual efficacy. In addition, potential neurobiological substrates for their actions are presented. It is concluded that pharmacological developments of mood-regulating or neuroprotective drugs can have cross benefit in co-morbid conditions of neuropsychiatric and neurodegenerative disorders and that inflammatory and neurotrophic factors play important roles in both conditions.

Current Neurogenic and Neuroprotective Strategies to Prevent and Treat Neurodegenerative and Neuropsychiatric Disorders.

The adult central nervous system is commonly known to have a very limited regenerative capacity. The presence of functional stem cells in the brain can therefore be seen as a paradox, since in other organs these are known to counterbalance cell loss derived from pathological conditions. This fact has therefore raised the possibility to stimulate neural stem cell differentiation and proliferation or survival by either stem cell replacement therapy or direct administration of neurotrophic factors or other proneurogenic molecules, which in turn has also originated regenerative medicine for the treatment of otherwise incurable neurodegenerative and neuropsychiatric disorders that take a huge toll on society. This may be facilitated by the fact that many of these disorders converge on similar pathophysiological pathways: excitotoxicity, oxidative stress, neuroinflammation, mitochondrial failure, excessive intracellular calcium and apoptosis. This review will therefore focus on the most promising achievements in promoting neuroprotection and neuroregeneration reported to date.

Perspectives for the treatment of sensorineural hearing loss by cellular regeneration of the inner ear.

Sensorineural hearing loss is a caused by the loss of the cochlear hair cells with the consequent deafferentation of spiral ganglion neurons. Humans do not show endogenous cellular regeneration in the inner ear and there is no exogenous therapy that allows the replacement of the damaged hair cells. Currently, treatment is based on the use of hearing aids and cochlear implants that present different outcomes, some difficulties in auditory discrimination and a limited useful life. More advanced technology is hindered by the functional capacity of the remaining spiral ganglion neurons. The latest advances with stem cell therapy and cellular reprogramming have developed several possibilities to induce endogenous regeneration or stem cell transplantation to replace damaged inner ear hair cells and restore hearing function. With further knowledge of the cellular and molecular biology of the inner ear and its embryonic development, it will be possible to use induced stem cells as in vitro models of disease and as replacement cellular therapy. Investigation in this area is focused on generating cellular therapy with clinical use for the treatment of profound sensorineural hearing loss.

Netrin-4 regulates thalamocortical axon branching in an activity-dependent fashion.

Axon branching is remodeled by sensory-evoked and spontaneous neuronal activity. However, the underlying molecular mechanism is largely unknown. Here, we demonstrate that the netrin family member netrin-4 (NTN4) contributes to activity-dependent thalamocortical (TC) axon branching. In the postnatal developmental stages of rodents, ntn4 expression was abundant in and around the TC recipient layers of sensory cortices. Neuronal activity dramatically altered the ntn4 expression level in the cortex in vitro and in vivo. TC axon branching was promoted by exogenous NTN4 and suppressed by depletion of the endogenous protein. Moreover, unc-5 homolog B (Unc5B), which strongly bound to NTN4, was expressed in the sensory thalamus, and knockdown of Unc5B in thalamic cells markedly reduced TC axon branching. These results suggest that NTN4 acts as a positive regulator for TC axon branching through activity-dependent expression.

Hypothalamic neurogenesis in the adult brain.

Adult-born new neurons are continuously added to the hippocampus and the olfactory bulb to serve aspects of learning and perceptual functions. Recent evidence establishes a third neurogenic niche in the ventral hypothalamic parenchyma surrounding the third ventricle that ensures the plasticity of specific brain circuits to stabilize physiological functions such as the energy-balance regulatory system. Hypothalamic lesion studies have demonstrated that regions associated with reproduction-related functions are also capable of recruiting newborn neurons to restore physiological functions and courtship behavior. Induced by lesion or other stimulation, elevated neurotrophic factors trigger neurogenic cascades that contribute to remodeling of certain neural circuits to meet specific transient functions. This insight raises the possibility that event-specific changes, such as increased GnRH, may be mediated by courtship-sensitive neurotrophic factors. We will discuss the potentially integral and ubiquitous roles of neurogenesis in physiological and biological phenomena, roles that await future experimental exploration.

Cooperative slit and netrin signaling in contralateralization of the mouse trigeminothalamic pathway.

Ascending somatosensory pathways are crossed pathways representing each side of the body in the contralateral neocortex. The principal sensory nucleus of the trigeminal nerve (PrV) relays the facial sensations to the contralateral somatosensory cortex via the ventrobasal thalamus. In the companion article (Kivrak and Erzurumlu [2012] J. Comp. Neurol. 12-0013) we described the normal development of the trigeminal lemniscal pathway in the mouse. In this study we investigated the role of midline axon navigation signals, the netrin and slit proteins. In situ hybridization assays revealed that both netrin and slit mRNAs are expressed along the midline facing the PrV axons and their receptors are expressed in developing PrV neurons. In wild-type mouse embryos, PrV axons cross the midline and take a sharp rostral turn heading toward the contralateral thalamus. Examination of trigeminal lemniscal axons in dcc knockout mice revealed absence of midline crossing between E11 and E15. However, a few axons crossed the midline at E17 and reached the contralateral thalamus, resulting in a bilateral PrV lemniscal pathway at P0. We also found that slit1, -2 or -3 single or double knockout mice have impaired development of the trigeminal-lemniscal pathway. These include axon stalling along the midline, running within the midline, and recrossing of axons back to the site of origin. Collectively, our studies indicate a cooperative role for netrin and slit proteins in midline attraction and crossing behavior of the ascending facial somatosensory projections during development.

Role of neurotrophins in the development and function of neural circuits that regulate energy homeostasis.

Members of the neurotrophin family, including nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5, and other neurotrophic growth factors such as ciliary neurotrophic factor and artemin, regulate peripheral and central nervous system development and function. A subset of the neurotrophin-dependent pathways in the hypothalamus, brainstem, and spinal cord, and those that project via the sympathetic nervous system to peripheral metabolic tissues including brown and white adipose tissue, muscle and liver, regulate feeding, energy storage, and energy expenditure. We briefly review the role that neurotrophic growth factors play in energy balance, as regulators of neuronal survival and differentiation, neurogenesis, and circuit formation and function, and as inducers of critical gene products that control energy homeostasis.

Neurite outgrowth of PC12 mutant cells induced by orange oil and d-limonene via the p38 MAPK pathway.

We studied the effects of natural essential oil on neurite outgrowth in PC12m3 neuronal cells to elucidate the mechanism underlying the action of the oils used in aromatherapy. Neurite outgrowth can be induced by nerve growth factor (NGF), where ERK and p38 MAPK among MAPK pathways play important roles in activating intracellular signal transduction. In this study, we investigated whether d-limonene, the major component of essential oils from oranges, can promote neurite outgrowth in PC12m3 cells, in which neurite outgrowth can be induced by various physical stimulations. We also examined by which pathways, the ERK, p38 MAPK or JNK pathway, d-limonene acts on PC12m3 cells. Our results showed that neurite outgrowth can be induced when the cells are treated with d-limonene. After treatment with d-limonene, we observed that p38 MAPK is strongly activated in PC12m3 cells, while ERK is weakly activated. In contrast, JNK shows little activity. A study using an inhibitor of p38 MAPK revealed that neurite outgrowth in PC12m3 cells is induced via the activation of p38 MAPK by d-limonene. The results thus indicate that d-limonene may promote neural cell differentiation mainly via activation of the p38 MAPK pathway.

[Advance in study on pharmacological mechanisms of Qingkailing injection in intervention of ischemic cerebral injury].

As a severe threat to human health, ischemic brain injury has a very complex pathological mechanism involving excitotoxic amino acids, oxygen free radical formation, nitric oxide (NO), Ca2+ overload and inflammation. Traditional Chinese medicine Qingkailing injection have shown good clinical efficacy in the treatment of cerebrovascular disease, and thus it is very significant to studies on its pharmacological mechanism. This essay summarizes relevant studies on pharmacological mechanism of a new compound traditional Chinese medicine Jingzhiqiangkailing (JZQKL) injection in treatment on cerebral ischemia, and explains the pharmacological mechanism of its single effective compounds and their compatibility in treatment of schemic brain injury in the aspects of regulating inflammatory response, neurotrophic factors, vascular protection, blood-brain barrier (BBB) protection and others, and thus providing information for further studies.

NeuriteQuant: an open source toolkit for high content screens of neuronal morphogenesis.

BACKGROUND: To date, some of the most useful and physiologically relevant neuronal cell culture systems, such as high density co-cultures of astrocytes and primary hippocampal neurons, or differentiated stem cell-derived cultures, are characterized by high cell density and partially overlapping cellular structures. Efficient analytical strategies are required to enable rapid, reliable, quantitative analysis of neuronal morphology in these valuable model systems. RESULTS: Here we present the development and validation of a novel bioinformatics pipeline called NeuriteQuant. This tool enables fully automated morphological analysis of large-scale image data from neuronal cultures or brain sections that display a high degree of complexity and overlap of neuronal outgrowths. It also provides an efficient web-based tool to review and evaluate the analysis process. In addition to its built-in functionality, NeuriteQuant can be readily extended based on the rich toolset offered by ImageJ and its associated community of developers. As proof of concept we performed automated screens for modulators of neuronal development in cultures of primary neurons and neuronally differentiated P19 stem cells, which demonstrated specific dose-dependent effects on neuronal morphology. CONCLUSIONS: NeuriteQuant is a freely available open-source tool for the automated analysis and effective review of large-scale high-content screens. It is especially well suited to quantify the effect of experimental manipulations on physiologically relevant neuronal cultures or brain sections that display a high degree of complexity and overlap among neurites or other cellular structures.

Oral Uncaria rhynchophylla (UR) reduces kainic acid-induced epileptic seizures and neuronal death accompanied by attenuating glial cell proliferation and S100B proteins in rats.

AIM OF THE STUDY: Epilepsy is a common clinical syndrome with recurrent neuronal discharges in cerebral cortex and hippocampus. Here we aim to determine the protective role of Uncaria rhynchophylla (UR), an herbal drug belong to Traditional Chinese Medicine (TCM), on epileptic rats. MATERIALS AND METHODS: To address this issue, we tested the effect of UR on kainic acid (KA)-induced epileptic seizures and further investigate the underlying mechanisms. RESULTS: Oral UR successfully decreased neuronal death and discharges in hippocampal CA1 pyramidal neurons. The population spikes (PSs) were decreased from 4.1 ± 0.4 mV to 2.1 ± 0.3 mV in KA-induced epileptic seizures and UR-treated groups, respectively. Oral UR protected animals from neuronal death induced by KA treatment (from 34 ± 4.6 to 191.7 ± 48.6 neurons/field) through attenuating glial cell proliferation and S100B protein expression but not GABAA and TRPV1 receptors. CONCLUSIONS: The above results provide detail mechanisms underlying the neuroprotective action of UR on KA-induced epileptic seizure in hippocampal CA1 neurons.

Laminar and areal expression of unc5d and its role in cortical cell survival.

The UNC-5 family of netrin receptors is known to regulate axon guidance, cell migration, and cell survival. We have previously demonstrated that unc5d, one of the UNC-5 family member genes, is specifically expressed in layer 4 of the developing rat neocortex (Zhong Y, Takemoto M, Fukuda T, Hattori Y, Murakami F, Nakajima D, Nakayama M, Yamamoto N. 2004. Identification of the genes that are expressed in the upper layers of the neocortex. Cereb Cortex. 14:1144-1152). However, the role of UNC5D in cortical development is still unknown. In this study, we revealed that unc5d was highly expressed in the primary sensory areas of the mouse neocortex at around postnatal day 7. Netrin-4 was also found to be predominantly expressed in layer 4 of the sensory cortex and sensory thalamic nuclei. Cell surface binding assay showed that netrin-4 protein bound to UNC5D-expressing cells. An in vitro study further demonstrated that cell death of unc5d-expressing layer 4 cells was reduced by exogenous application of netrin-4 protein, whereas UNC5D is not sufficient to mediate the effect of netrin-4 in deep layer cells. Taken together, these results suggest that UNC5D is primarily expressed by layer 4 cells in the primary sensory areas of the developing neocortex and may mediate the effect of netrin-4 on cortical cell survival in a lamina-specific manner.

Neuroendocrine regulatory peptide-1 and -2: novel bioactive peptides processed from VGF.

Neuroendocrine regulatory peptides (NERP)-1 and NERP-2 are derived from distinct regions of VGF, a neurosecretory protein that was originally identified as a product of a nerve growth factor-responsive gene in rat PC12 cells. The amino acid length of human NERP-1 is 26, and that of rat NERP-1 is 25. Human and rat NERP-2 are both 38 amino acid peptides. NERPs colocalize with vasopressin in the storage granules of the paraventricular and supraoptic nuclei in the hypothalamus of both rats and humans. Administration of NERPs suppresses hypertonic saline- or angiotensin II-induced vasopressin release from the hypothalamus and pituitary. Thus, VGF is a precursor of multiple bioactive peptides with diverse neuroendocrine functions, and NERPs are novel hypothalamic peptides involved in the control of body fluid homeostasis by regulating vasopressin release.

Netrin-4 regulates angiogenic responses and tumor cell growth.

Netrin-4 is a 628 amino acid basement membrane component that promotes neurite elongation at low concentrations but inhibits neurite extension at high concentrations. There is a growing body of literature suggesting that several molecules, including netrins, are regulators of both neuronal and vascular growth. It is believed that molecules that guide neural growth and development are also involved in regulating morphogenesis of the vascular tree. Further, netrins have recently been implicated in controlling epithelial cell branching morphogenesis in the breast, lung and pancreas. Characterization of purified netrin-4 in in vitro angiogenesis assays demonstrated that netrin-4 markedly inhibits HMVEC migration and tube formation. Moreover, netrin-4 inhibits proliferation of a variety of human tumor cells in vitro. Netrin-4 has only modest effects on proliferation of endothelial and other non-transformed cells. Netrin-4 treatment results in phosphorylation changes of proteins that are known to control cell growth. Specifically, Phospho-Akt-1, Phospho-Jnk-2, and Phospho-c-Jun are reduced in tumor cells that have been treated with netrin-4. Together, these data suggest a potential role for netrin-4 in regulating tumor growth.

[Atopic dermatitis and stress? How do emotions come into skin?]. / Neurodermitis und Stress. Wie kommen Gefühle in die Haut?

It is widely accepted, that stress can induce or exacerbate atopic dermatitis. The physiological mechanisms that mediate this negative influence of stress on atopic dermatitis are not clearly understood. This topic has been actively investigated in recent years focusing on neuroimmunological, psychoendocrinological studies and examination of integrity and function of skin barrier under stress. Different neuropeptides and neurotrophins seem to play an important role in stress-induced neurogenic inflammation and connection of nervous and immune system. Mast cells play a key role in the development of inflammatory reaction to stress. Skin barrier is altered by stress by means of increased cortisol level. Thereby lamellar body secretion is decreased and epidermal expression of antimicrobial peptides (beta-defensin and cathelicidin) is down-regulated. We review recent investigations in this field.

[The messengers from peripheral nervous system to central nervous system: involvement of neurotrophins and cytokines in the mechanisms of acupuncture].

Neurotrophic factors and cytokines are involved in the regulation of neuronal survival, axonal myelination, and synaptic plasticity in both central nervous system (CNS) and peripheral nervous system (PNS). The members of the neurotrophic factor family include nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4/5 (NT-4/5). These molecules bind to two types of receptors: (1) tyrosine kinase receptors (TrkA, TrkB, TrkC) and 2) common neurotrophin receptor (p 75 NTR). The internalization and retrograde axonal transport of neurotrophin receptors are important for their signal transduction supporting neuronal survival, synaptic plasticity, and axonal myelination. In addition, a growing body of data suggests that neurotrophins are involved in the pathophysiologicl courses of inflammatory pain, neurodegenerative disease, and psychiatric diseases. Cytokines, including IL-1, IL-2, IL-6, and TNF-alpha,are important mediators of the immune response and play a key role in the diseases by acting on inflammatory immune cells, neuronal cells, muscle cells, and vessel cells. Interestingly, some cytokines (e.g. TNF-alpha, IL-2, TGF-beta) are also able to regulate synaptic plasticity and affect CNS functions. The neurotrophins and cytokines release in response to various stimuli, such as electronic stimulation, or inflammation. This crosstalk from PNS to CNS is involved in the pathophysiology of many human diseases and may contribute to the effects of acupuncture. Based on our knowledge to neurotrophins and cytokines, we proposed the neurotrophin/cytokine hypothesis for the mechanism of acupuncture. This hypothesis may initiate the discussion on the possible roles of neurotrophins/cytokines in the therapeutic effects of acupuncture and shed light to the discovery of mechanism of acupuncture in the treatment of devastating diseases.