Sesamol Attenuates Scopolamine-Induced Cholinergic Disorders, Neuroinflammation, and Cognitive Deficits in Mice.

Alzheimer's disease (AD) is a neurodegenerative disease, characterized by memory loss and cognitive deficits accompanied by neuronal damage and cholinergic disorders. Sesamol, a lignan component in sesame oil, has been proven to have neuroprotective effects. This research aimed to investigate the preventive effects of sesamol on scopolamine (SCOP)-induced cholinergic disorders in C57BL/6 mice. The mice were pretreated with sesamol (100 mg/kg/d, p.o.) for 30 days. Behavioral tests indicated that sesamol supplement prevented SCOP-induced cognitive deficits. Sesamol enhanced the expression of neurotrophic factors and postsynaptic density (PSD) in SCOP-treated mice, reversing neuronal damage and synaptic dysfunction. Importantly, sesamol could balance the cholinergic system by suppressing the AChE activity and increasing the ChAT activity and M1 mAChR expression. Sesamol treatment also inhibited the expression of inflammatory factors and overactivation of microglia in SCOP-treated mice. Meanwhile, sesamol improved the antioxidant enzyme activity and suppressed oxidative stress in SCOP-treated mice and ameliorated the oxidized cellular status and mitochondrial dysfunction in SCOP-treated SH-SY5Y cells. In conclusion, these results indicated that sesamol attenuated SCOP-induced cognitive dysfunction via balancing the cholinergic system and reducing neuroinflammation and oxidative stress.

Novel targets for parkinsonism-depression comorbidity.

With the aging population growing and the incidence of neurodegenerative diseases on the rise, the researchers in the field are yet more urgently challenged to slow and/or reverse the devastating consequences of such progression. The challenge is further enforced by psychiatric co-morbid conditions, particularly the feeling of despair in these population. Fortunately, as our understanding of the neurobiological substrates of maladies affecting the central nervous system increases, more therapeutic options are also presented. In this short review while providing evidence of shared biological substrates between Parkinson's disease and depression, novel therapeutic targets and drugs are suggested. The emphasis will be on neuroplasticity underscored by roles of neurotrophic and inflammatory factors. Examples of few therapeutic drugs as well as future directions are also touched upon.

Neuroprotective strategies for retinal disease.

Diseases that affect the eye, including photoreceptor degeneration, diabetic retinopathy, and glaucoma, affect 11.8 million people in the US, resulting in vision loss and blindness. Loss of sight affects patient quality of life and puts an economic burden both on individuals and the greater healthcare system. Despite the urgent need for treatments, few effective options currently exist in the clinic. Here, we review research on promising neuroprotective strategies that promote neuronal survival with the potential to protect against vision loss and retinal cell death. Due to the large number of neuroprotective strategies, we restricted our review to approaches that we had direct experience with in the laboratory. We focus on drugs that target survival pathways, including bile acids like UDCA and TUDCA, steroid hormones like progesterone, therapies that target retinal dopamine, and neurotrophic factors. In addition, we review rehabilitative methods that increase endogenous repair mechanisms, including exercise and electrical stimulation therapies. For each approach, we provide background on the neuroprotective strategy, including history of use in other diseases; describe potential mechanisms of action; review the body of research performed in the retina thus far, both in animals and in humans; and discuss considerations when translating each treatment to the clinic and to the retina, including which therapies show the most promise for each retinal disease. Despite the high incidence of retinal diseases and the complexity of mechanisms involved, several promising neuroprotective treatments provide hope to prevent blindness. We discuss attractive candidates here with the goal of furthering retinal research in critical areas to rapidly translate neuroprotective strategies into the clinic.

Lindersin B from Lindernia crustacea induces neuritogenesis by activation of tyrosine kinase A/phosphatidylinositol 3 kinase/extracellular signal-regulated kinase signaling pathway.

BACKGROUND: Neurotrophic factors such as nerve growth factor (NGF) play important roles in nervous system. NGF is a potential therapeutic drug for treatment of neurodegenerative diseases. However, because of physicochemical property, NGF cannot pass through the blood-brain barrier (BBB). Hence, small molecules which exhibit NGF-mimic activity and can pass through the BBB are considered to be promising drug candidates for treatment of such diseases. PURPOSE: The present study was designed to isolate NGF-mimic substance from extract of natural products, determine their structures and investigate mechanism of action of the active substance. METHODS: Extract of Lindernia crustacean was partitioned between water and ethyl acetate to obtain water layer and ethyl acetate layer samples, respectively, and then evaluated their neuritogenic activity in PC12 cells. The active sample was separated by open columns, followed by HPLC purification to obtain active compound. Then, specific inhibitors were used to investigate signaling pathway of neurite outgrowth induced by the active compound. Finally, western blot analysis was performed to confirm the pathway proposed by inhibitor experiments. RESULTS: The ethyl acetate layer sample of extract of Lindernia crustacea exhibited significant neuritogenic activity. Two new compounds, named as linderside A and lindersin B, were isolated; their structures were elucidated by spectroscopic and chemical derivatization methods. Linderside A is a cucurbitane glycoside, whereas lindersin B is a cucurbitane triterpenoid. Each compound has an unusual isopentene unit, namely, a double bond bound to an unmodified isopropyl group at the end of cucurbitane triterpenoid side chain. Among them, lindersin B induced significant neurite outgrowth in PC12 cells, while linderside A was inactive against PC12 cells. Western blotting analysis results showed that lindersin B-induced neuritogenic activity depended on the activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK). Moreover, tyrosine kinase A (TrKA) and phosphatidylinositol 3 kinase (PI3K) were also involved in the signaling pathway. CONCLUSIONS: Two new cucurbitane triterpenoids, linderside A and lindersin B, were isolated from Lindernia crustacean. Neurite outgrowth induced by lindersin B in PC12 cells depends on activation of TrkA/PI3K/ERK signaling pathway.

Therapeutic Potential of Genipin in Central Neurodegenerative Diseases.

Central neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are one of the biggest health problems worldwide. Currently, there is no cure for these diseases. The Gardenia jasminoides fruit is a common herbal medicine in traditional Chinese medicine (TCM), and a variety of preparations are used as treatments for central nervous system (CNS) diseases. Pharmacokinetic studies suggest genipin is one of the main effective ingredients of G. jasminoides fruit extract (GFE). Accumulated research data show that genipin possesses a range of key pharmacological properties, such as anti-inflammatory, neuroprotective, neurogenic, antidiabetic, and antidepressant effects. Thus, genipin shows therapeutic potential for central neurodegenerative diseases. We review the pharmacological actions of genipin for the treatment of neurodegenerative diseases of the CNS. We also describe the potential mechanisms underlying these effects.

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.

Nonpeptide neurotrophic agents useful in the treatment of neurodegenerative diseases such as Alzheimer's disease.

Developed regions, including Japan, have become "aged societies," and the number of adults with senile dementias, such as Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease, has also increased in such regions. Neurotrophins (NTs) may play a role in the treatment of AD because endogenous neurotrophic factors (NFs) prevent neuronal death. However, peptidyl compounds have been unable to cross the blood-brain barrier in clinical studies. Thus, small molecules, which can mimic the functions of NFs, might be promising alternatives for the treatment of neurodegenerative diseases. Natural products, such as or nutraceuticals or those used in traditional medicine, can potentially be used to develop new therapeutic agents against neurodegenerative diseases. In this review, we introduced the neurotrophic activities of polyphenols honokiol and magnolol, which are the main constituents of Magnolia obovata Thunb, and methanol extracts from Zingiber purpureum (BANGLE), which may have potential therapeutic applications in various neurodegenerative disorders.

Synergistic antitumor effect of recombinant adeno-associated virus-mediated pigment epithelium-derived factor with hyperthermia on solid tumor.

Adeno-associated virus (AAV) is an ideal choice for gene delivery; however, its further development has been limited owing to its low transduction efficiency. DNA-damaging agents can improve AAV-mediated transgene expression. Hyperthermia, as one of the oldest documented tumor treatment modalities, can cause DNA damage as well. However, combined treatment consisting of hyperthermia and AAV-mediated gene therapy has not been reported yet. In this work we investigated whether therapy consisting of AAV-mediated pigment epithelium-derived factor (PEDF) delivery combined with hyperthermia has synergistic antitumor effect on established solid tumors. We produced the recombinant AAV encoding PEDF (rAAV-PEDF). The therapeutic effect of rAAV-PEDF plus hyperthermia was evaluated in a subcutaneous fibrosarcoma mouse model, and the possible mechanism of antitumor effect was investigated. We found that rAAV-PEDF could infect a murine fibrosarcoma cell line (Meth-A) and express PEDF protein with bioactivity in vitro. In addition, in vivo experiments suggested that the combination of rAAV-PEDF with hyperthermia could significantly suppress tumor growth and prolong survival time of treated mice. Immunofluorescence studies indicated that the combination therapy could inhibit angiogenesis and induce apoptosis in tumor tissues. An immunohistochemistry assay of tumor tissue showed that PEDF expression in the combined treatment group was significantly higher than in the rAAV-PEDF group, which implied that hyperthermia could improve the expression of PEDF protein in vivo. No significant differences were observed in each group by hematoxylin-eosin staining of major organs, serum chemistry test, and complete blood assay. These results indicate that the combination of rAAV-PEDF with hyperthermia has synergistic therapeutic effects on established solid tumors, with no side effects. In addition, hyperthermia could improve AAV-mediated transgene expression, which suggests that hyperthermia could serve as a promising adjunctive therapy for AAV-mediated gene therapy.

Most effective adjuvant treatments after surgery in peripheral nerve laceration: Systematic review of the literature on rodent models.

Surgical repair alone does not lead to satisfactory recovery after nerve laceration injury, yet no adjuvant clinical treatments are available. The goal of this review is to systematically survey all adjuvant treatments after surgery investigated in rat and mouse models. Both PubMed and Embase were explored with a systematic bibliographic search algorithm. Inclusion criteria consisted of treatments applied to rats or mice after complete transection and microsurgical repair of lower-limb motor or mixed nerves. Effect size statistics enabled numerical comparison between outcomes of treated and untreated animals and ranked the best treatments. 1,553 articles were found according to our search strategies, and 22 of them corresponded to our pre-defined inclusion criteria. After data extraction and analysis, the top 3 adjuvant strategies in terms of combined average effect size were citicoline, neurotrophin-4, and nitric oxide synthesis inhibitor, with values of 5.52, 5.14 and 4.08, respectively. Definitive treatment comparison was difficult due to the lack of uniformity in outcome evaluation in the experiments performed. Animal studies, comparing treatments administered within the same experimental protocol, are needed to truly assess efficiency and to provide solid recommendations for future clinical investigation.

Involvement of pigment epithelium-derived factor, docosahexaenoic acid and neuroprotectin D1 in corneal inflammation and nerve integrity after refractive surgery.

Alterations in corneal innervations result in impaired corneal sensation, severe dry eye and damage to the epithelium that may in turn lead to corneal ulcers, melting and perforation. These alterations can occur after refractive surgery. We have discovered that pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA or the docosanoid bioactive neuroprotectin D1 (NPD1)) induces nerve regeneration after corneal surgery that damages the stromal nerves. We found that PEDF is released from corneal epithelial cells after injury, and when DHA is provided to the cells it stimulates the biosynthesis of NPD1 by an autocrine mechanism. The combination of PEDF plus DHA also decreased the production of leukotriene B4 (LTB4), a neutrophil chemotactic factor, thereby decreasing the inflammation induced after corneal damage. These studies suggest that PEDF plus DHA and its derivative NPD1 hold promise as a future treatment to restore a healthy cornea after nerve damage.

The protective effects of Achyranthes bidentata polypeptides on rat sciatic nerve crush injury causes modulation of neurotrophic factors.

Pharmacological treatment is a therapeutic approach to improving nerve regeneration and functional recovery after peripheral nerve crush injury. The objective of the present study was to investigate the effects of the polypeptides isolated from Achyranthes bidentata Blume (abbreviated as ABPP) on rat sciatic crush injury and to test the possible involvement of neurotrophic factors. After surgical crush injury, rats received daily intraperitoneal injection of 0.2 ml saline containing 2 mg ABPP, 1 µg nerve growth factor (NGF) or no additive. The results from walking track analysis, electrophysiological assessment and histological evaluation indicated that the repair outcomes by ABPP treatment were close to those by NGF treatment, but better than those by treatment with saline alone. The quantitative real-time RT-PCR was used to monitor the mRNA expression of growth associated protein in the crush nerves and the mRNA expression of NGF, brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), tyrosine kinase (Trk)A and TrkB in the dorsal root ganglia (DRGs) at L4-L6. The mRNA expression of these genes in the crush nerve sample and DRGs sample was higher after treatment with ABPP or NGF than after treatment with saline alone. Our findings suggest that ABPP might protect peripheral nerve against crush injury through stimulating release of neurotrophic factors and the other cytokines.

T-817MA, a novel neurotrophic agent, ameliorates loss of GABAergic parvalbumin-positive neurons and sensorimotor gating deficits in rats transiently exposed to MK-801 in the neonatal period.

T-817MA [1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}azetidin-3-ol maleate] is a newly synthesized neuroprotective agent for the treatment of psychiatric disorders characterized by cognitive disturbances, such as Alzheimer's disease. Cognitive impairment has also been suggested to be a cardinal feature of schizophrenia. We sought to determine whether T-817MA would ameliorate sensorimotor gating deficits and loss of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) neurons in the brain of rats transiently exposed to MK-801, an N-methyl-d-aspartate receptor blocker, in the neonatal stage, as an animal model of schizophrenia. Prepulse inhibition (PPI) was examined in rats treated neonatally with MK-801 (postnatal day; PD 7-10, 0.2 mg/kg/day, s.c.) or vehicle at PD 35 and PD 63. The number of PV-positive GABAergic neurons in the medial prefrontal cortex (mPFC) and the hippocampus was measured after the behavioral assessments. T-817MA (10 or 20 mg/kg) or vehicle was administered for 14 days (on PD 49-62). Administration of T-817MA at 20 mg/kg, but not 10 mg/kg, ameliorated PPI deficits and completely reversed the decrease in the number of PV-positive GABAergic neurons in rats given MK-801. These results indicate that T-817MA may provide a novel therapeutic approach for the treatment of cognitive deficits of schizophrenia.

A culture model for neurite regeneration of human spinal cord neurons.

Effective therapeutic interventions for injuries of the central nervous system such as spinal cord injury are still unavailable, having a great impact on the quality of life of victims and their families, as well as high costs in medical care. Animal models of spinal cord injury are costly, time-consuming and labor-intensive, making them unsuitable for screening large numbers of experimental conditions. Thus, culture models that recapitulate key aspects of neuronal changes in central nervous system injuries are needed to gain further understanding of the pathological and regenerative mechanisms involved, as well as to accelerate the screening of potential therapeutic agents. In this study we differentiated adherent cultures of dissociated human fetal spinal cord neural precursors into postmitotic neurons which we could then detach from culture plates and successfully freeze down in a viable state. When replated in neuronal medium without neurodifferentiating factors, these ready-to-use human spinal cord neurons remained viable, postmitotic and regenerated neurites in a cell density-dependent manner. Insulin-like growth factor 1 and growth hormone had no effect on neurite regeneration while brain-derived neurotrophic factor increased both the number of cells with neurites as well as the average neurite length. Our model can be applied to investigate factors involved in neuroregeneration of the human spinal cord and since adherent dissociated cell cultures are used, this system has significant potential as a screening platform for therapeutic agents to treat spinal cord injury.

Electroacupucture and nerve growth factor: potential clinical applications.

The nerve growth factor (NGF) is a neurotrophin regulating the survival and function peripheral sensory and sympathetic neurons and of forebrain cholinergic neurons. Both peripheral neuropathies and brain cholinergic dysfunctions could benefit from NGFbased therapies, but the clinical use of NGF has been so far hampered by the development of important side effects, like hyperalgesia and autonomic dysfunctions. Acupuncture is a therapeutic technique and is a part of traditional Chinese medicine. Western descriptions of the clinical efficacy of acupuncture on pain, inflammation, motor dysfunction, mood disorders, and seizures are based on the stimulation of several classes of sensory afferent fibers and the consequent activation of physiological processes similar to those resulting from physical exercise or deep massage. Recently, it has been shown that peripheral sensory stimulation by electroacupuncture (EA) could improve brain NGF availability and utilization, at the same time counteracting the major sideeffects induced by NGF administration. This review focuses on the emerging links between EA and NGF with special emphasis on the work carried out in the last decade in our laboratory, investigating the role of NGF as a mediator of EA effects in the central nervous system and as a modulator of sensory and autonomic activity.

Non-surgical therapies for peripheral nerve injury.

BACKGROUND: Non-surgical approaches have been developed to enhance nerve recovery, which are complementary to surgery and are an adjunct to the reinnervation process. SOURCES OF DATA: A search of PubMed, Medline, CINAHL, DH data and Embase databases was performed using the keywords 'peripheral nerve injury' and 'treatment'. AREAS OF CONTROVERSY: Most of the conservative therapies are focused to control neuropathic pain after nerve tissue damage. Only physical therapy modalities have been studied in humans and their effectiveness is not proved. GROWING POINTS: Many modalities have been experimented with to promote nerve healing and restore function in animal models and in vitro studies. Despite this, none have been actually translated into clinical practice. AREAS TIMELY FOR DEVELOPING RESEARCH: The hypotheses proved in animals and in vitro should be translated to human clinical practice.

A virus-like particle-based anti-nerve growth factor vaccine reduces inflammatory hyperalgesia: potential long-term therapy for chronic pain.

Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. For a substantial proportion of patients, conventional drug treatments do not provide adequate pain relief. Consequently, novel approaches to pain management, involving alternative targets and new therapeutic modalities compatible with chronic use, are being sought. Nerve growth factor (NGF) is a major mediator of chronic pain. Clinical testing of NGF antagonists is ongoing, and clinical proof of concept has been established with a neutralizing mAb. Active immunization, with the goal of inducing therapeutically effective neutralizing autoreactive Abs, is recognized as a potential treatment option for chronic diseases. We have sought to determine if such a strategy could be applied to chronic pain by targeting NGF with a virus-like particle (VLP)-based vaccine. A vaccine comprising recombinant murine NGF conjugated to VLPs from the bacteriophage Qß (NGFQß) was produced. Immunization of mice with NGFQß induced anti-NGF-specific IgG Abs capable of neutralizing NGF. Titers could be sustained over 1 y by periodic immunization but declined in the absence of boosting. Vaccination with NGFQß substantially reduced hyperalgesia in collagen-induced arthritis or postinjection of zymosan A, two models of inflammatory pain. Long-term NGFQß immunization did not change sensory or sympathetic innervation patterns or induce cholinergic deficits in the forebrain, nor did it interfere with blood-brain barrier integrity. Thus, autovaccination targeting NGF using a VLP-based approach may represent a novel modality for the treatment of chronic pain.

Enhancement of nose-brain delivery of therapeutic agents for treating neurodegenerative diseases using peppermint oil.

The nose-brain pathway is a potential route for drug delivery as it bypasses the brain barriers. The main objective of this study was to investigate the efficacy of peppermint oil in enhancing the bioavailability of intranasally administered neurotrophins like nerve growth factor (NGF). The effect of different concentrations of peppermint oil (PO) on the delivery of NGF across bovine olfactory epithelium was studied in vitro using Franz diffusion cells. Trans-olfactory epithelial electrical resistance (TEER) was measured to assess the permeability status of the bovine olfactory epithelium. The bioavailability of intranasally administered formulations in rat hippocampus was studied by carrying out brain microdialysis in male Sprague-Dawley rats. Peppermint oil at concentrations of 0.05, 0.1 and 0.5% v/v enhanced the in vitro transport of NGF by 5, 7 and 8 fold, respectively. In vivo studies employing brain microdialysis in rats demonstrated that intranasal administration of NGF formulation with 0.5% PO enhanced the bioavailability by approximately 8 fold compared to rats administered with NGF alone. The bioavailability of NGF in the brain could be enhanced by intranasal administration of peppermint oil.

Investigational agents for the irritable bowel syndrome.

IMPORTANCE OF THE FIELD: Irritable bowel syndrome (IBS) is a common disorder with significant health and economic consequences. The etiology of IBS is complex and appears to be multifactorial. Traditional IBS therapies have been directed primarily at the relief of individual symptoms but have been largely disappointing. This has triggered the search for newer treatment strategies with improved patient outcomes. AREAS COVERED IN THIS REVIEW: Enhanced knowledge about the putative pathophysiology of IBS has allowed the identification of new mechanistic targets for treatment. Our aim is to review emerging and promising drugs in the treatment of IBS based on disease pathophysiology. Data were extracted using Medline and PubMed search engines until January 2010. Abstracts were identified through 'Web of Science' and abstract supplements of major gastrointestinal scientific meetings. Drugs were classified according to mechanism of action and those with efficacy in trials involving human subjects examined. WHAT THE READER WILL GAIN: Additional insight into the pathophysiology as well as current and prospective treatments of IBS. TAKE HOME MESSAGE: A multitude of putative drug targets have been identified and some novel treatments have progressed through to human clinical trials, but very few will be approved for the market in the near future. Moreover, and in keeping with the complex and multifactorial nature of this syndrome, it is unlikely that there will be one dominant and universally effective form of therapy for all IBS patients.

Recovery of function in humans: cortical stimulation and pharmacological treatments after stroke.

In this contribution, we first provide an overview of general principles of reorganisation in the human brain, and point out possible biomarkers of recovery. Subsequently, we expand on possibilities of adjuvant therapy in human rehabilitation using cortical stimulation and pharmacological treatments. Finally, we suggest future directions for research in this field.

The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis.

Lithium has been and continues to be the mainstay of bipolar disorder (BD) pharmacotherapy for acute mood episodes, switch prevention, prophylactic treatment, and suicide prevention. Lithium is also the definitive proof-of-concept agent in BD, although it has recently been studied in other psychoses as well as diverse neurodegenerative disorders. Its neurotrophic effects can be viewed as a unifying model to explain several integrated aspects of the pathophysiology of mood disorders and putative therapeutics for those disorders. Enhancing neuroprotection (which directly involves neurotrophic effects) is a therapeutic strategy intended to slow or halt the progression of neuronal loss, thus producing long-term benefits by favorably influencing outcome and preventing either the onset of disease or clinical decline. The present article: (i) reviews what has been learned regarding lithium's neurotrophic effects since Cade's original studies with this compound; (ii) presents human data supporting the presence of cellular atrophy and death in BD as well as neurotrophic effects associated with lithium in human studies; (iii) describes key direct targets of lithium involved in these neurotrophic effects, including neurotrophins, glycogen synthase kinase 3 (GSK-3), and mitochondrial/endoplasmic reticulum key proteins; and (iv) discusses lithium's neurotrophic effects in models of apoptosis and excitotoxicity as well as its potential neurotrophic effects in models of neurological disorders. Taken together, the evidence reviewed here suggests that lithium's neurotrophic effects in BD are an example of an old molecule acting as a new proof-of-concept agent. Continued work to decipher lithium's molecular actions will likely lead to the development of not only improved therapeutics for BD, but to neurotrophic enhancers that could prove useful in the treatment of many other illnesses.