Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of MANF (mesencephalic astrocyte-derived neurotrophic factor) and HSPA5 (heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 were transcriptionally induced by liganded estrogen receptor ß and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor ß-specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of MANF/HSPA5 in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis.

Demonstration of ameliorating effect of vardenafil through its anti-inflammatory and neuroprotective properties in autism spectrum disorder induced by propionic acid on rat model.

INTRODUCTION: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with complex etiology. In this study, we aimed to determine the ameliorating effects of vardenafil in the ASD rat model induced by propionic acid (PPA) in terms of neurobehavioral changes and also support these effects with histopathological changes, brain biochemical analysis and magnetic resonance spectroscopy (MRS) findings. MATERIALS AND METHODS: Twenty-one male rats were randomly assigned into three groups. Group 1 (control, 7 rats) did not receive treatment. Rats in groups 2 and 3 were given PPA at the dose of 250 mg/kg/day intraperitoneally for 5 days. After PPA administration, animals in group 2 (PPAS, 7 rats) were given saline and animals in group 3 (PPAV, 7 rats) were given vardenafil. Behavioral tests were performed between the 20th and 24th days of the study. The rats were taken for MRS on the 25th day. At the end of the study, brain levels of interleukin-2 (IL-2), IL-17, tumor necrosis factor-α, nerve growth factor, cGMP and lactate levels were measured. In the cerebellum and the CA1 and CA3 regions of the hippocampus, counts of neurons and Purkinje cells and glial fibrillary acidic protein (associated with gliosis) were evaluated histologically. RESULTS: Three chamber sociability and passive avoiding test, histopathological results, lactate levels derived from MRS, and biochemical biomarkers revealed significant differences among the PPAV and PPAS groups. CONCLUSION: We concluded that vardenafil improves memory and social behaviors and prevent loss of neuronal and Purkinje cell through its anti-inflammatory and neuroprotective effect.

Phase 1b Randomized Controlled Study of Short Course Topical Recombinant Human Nerve Growth Factor (rhNGF) for Neuroenhancement in Glaucoma: Safety, Tolerability, and Efficacy Measure Outcomes.

PURPOSE: No approved therapies directly target retinal ganglion cells (RGCs) for neuroprotection or neuroenhancement in glaucoma. Recombinant human nerve growth factor (rhNGF) has been shown to promote RGC survival and function in animal models of optic neuropathy. Here we evaluate the safety, tolerability, and efficacy of short-term, high-dose rhNGF eye drops versus placebo in a cohort of glaucoma patients. DESIGN: This was a prospective, phase 1b, single-center, randomized, double-masked, vehicle-controlled, parallel-group study. METHODS: This study was designed to assess safety and tolerability as well as short-term neuroenhancement of structure and function (clinicaltrials.gov NCT02855450). A total of 60 open-angle glaucoma patients were randomized 40:20 to receive either 180 µg/mL rhNGF or vehicle control eye drops in both eyes, 3 times daily for 8 weeks, with a 24-week post-treatment follow-up. One eye was officially selected as the study eye, although both eyes were studied and dosed. Primary endpoints were safety, as assessed by adverse events, and tolerability, as assessed by patient-reported outcomes. Secondary outcome measures included best corrected visual acuity (BCVA), Humphrey visual field, electroretinograpy (ERG), and optical coherence tomography (OCT) of retinal nerve fiber layer (RNFL) thickness at baseline, after 8 weeks of treatment, and at 4 and 24 weeks after treatment (12 and 32 weeks total). RESULTS: Of the 60 randomized patients, 23 were female (38%) and the average age was 66.1 years. Through week 32, there were no treatment-related serious adverse events, including no unexpectedly severe progression of optic neuropathy, no adverse events affecting ocular function or pressure, and no drug-related systemic toxicity. Topical high-dose rhNGF was tolerated well, with a low level of symptom burden mainly eliciting periocular ache (in 52% of treated group and 5% of placebo group) and only 3 patients (7.5%) discontinuing treatment because of discomfort, of whom 1 patient (2.5%) prematurely withdrew from the study. There were no statistically significant differences in global indices of Humphrey visual field and no meaningful differences in total, quadrant, or clock-hour mean RNFL thickness between the groups, although both of these function and structure measures showed nonsignificant trends toward significance in favor of rhNGF. Real-world participant data was used to generate an estimate of cohort size needed to power subsequent studies. CONCLUSIONS: Use of rhNGF is safe and tolerable in a topical 180-µg/mL formulation. Although no statistically significant short-term neuroenhancement was detected in this trial, given the strong effects of NGF in preclinical models and the trends detected in this study, analysis for efficacy in a neuroprotection trial is warranted. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Estado nutricional de indivíduos com Comprometimento Cognitivo Leve e Doença de Alzheimer em relação ao Selênio e sua associação com parâmetros que predispõem ao declínio cognitivo / Nutritional status of subjects with mild cognitive impairment and Alzheimer's disease in relation to selenium and its association with paramenters that predispose to cognitive decline

A Doença de Alzheimer (DA) é a principal forma de demência e um dos grandes desafios no sistema de saúde do século 21. O Comprometimento Cognitvo Leve (CCL) é um estágio que antecede a DA e que compartilha algumas vias metabólicas em comum. A fisiopatologia da DA é caracterizada pela ampla morte neuronal e pela presença de placas neuríticas e emaranhados neurofibrilares, respectivamente relacionadas ao acúmulo de peptídeo beta amiloide (Aß) em tecidos cerebrais e alterações no citoesqueleto que se originam da hiperfosforilação da proteína tau nos neurônios. Algumas linhas de evidência sustentam a hipótese de que o estresse oxidativo, nitrosativo e a inflamação tenham um papel importante na patogênese tanto do DA como do CCL. O selênio, mineral essencial ao ser humano, encontra-se incorporado ao sítio ativo de 25 selenoproteínas, das quais pelo menos um terço apresenta papel antioxidante, além de potencialmente modularem o sistema inflamatório. Deste modo, o estado nutricional adequado dos indivíduos relativo ao selênio, parece exercer efeito neuroprotetor, reduzindo o risco para o CCL e DA e retardando a progressão destas doenças. A entrega de selênio para o cérebro se dá pela interação da selenoproteína P (SELENOP) com o receptor de apolipoproteína E2 (ApoER2). A apolipoproteína E (ApoE) também interage com o ApoER2 no metabolismo de lipídeos. Assim, pode-se pensar que indivíduos portadores do polimorfismo do gene da apolipoproteína E ε4 (APOE ε4), o principal polimorfismo genético para o aumento no risco de desenvolvimento de DA, possam ter essa entrega de selênio prejudicada para o cérebro uma vez que os receptores ApoER2 dos portadores do polimorfismo de APOE ε4 são sequestrados para compartimentos intracelulares, sendo menos expressos na membrana plasmática e portanto diminuindo a interação com a SELENOP. Este trabalho teve por objetivo avaliar se a distribuição do selênio no plasma e líquor de indivíduos portadores de CCL e DA é afetada pelo alelo APOE ε4, avaliar se o estado nutricional do indivíduo em relação ao selênio afeta marcadores de assinatura biológica para DA (peptídeo beta amilóide, proteína tau e proteína tau fosforilada) e concentrações de citocinas inflamatórias. Para tanto, foram selecionadas amostras de plasma e líquor do banco de material biológico do Instituto de Psiquiatria da FMUSP, sendo 14 indivíduos do grupo CCL, 28 indivíduos do grupo DA e 28 indivíduos controles, de ambos os gêneros, com idade acima de 60 anos e residentes na cidade de São Paulo. Foram avaliados os seguintes marcadores: concentrações de selênio no plasma e líquor, concentrações SELENOP no plasma e líquor, citocinas inflamatórias, fator neurotrófico derivado do cérebro (BDNF) e marcadores de assinatura biológica para DA. Não foi evidenciada diferença entre os três diferentes grupos em relação ao selênio e a SELENOP da mesma forma que não houve influência do genótipo APOE ε4 nas concentrações de selênio e SELENOP, porém houve uma tendência de menores concentrações de selênio plasmático nos carreadores do alelo APOE ε4. Também houve uma tendência a uma menor pontuação nos testes MMSE e CAMCOG em indivíduos com menores concentrações plasmáticas de selênio. Não se evidenciou que o estado nutricional dos indivíduos em relação ao selênio influencie as concentrações de marcadores para assinatura biológica para DA e de citocinas inflamatórias, com exceção da IL-10 que apresentou correlação positiva com SELENOP plasmática. A partir desses resultados, conclui-se que o estado nutricional dos indivíduos relativo ao selênio parece não ter influencia significativa em aspectos do CCL e DA e que sua distribuição não é alterada pelo genótipo APOE ε4

Alzheimer's disease (AD) is the main form of dementia and one of the major challenges in the healthcare system of the 21st century. Mild Cognitive Impairment (MCI) is a stage that precedes AD and shares common metabolic pathways. The pathophysiology of AD is characterized by extensive neuronal death, presence of neuritic plaques and neurofibrillary tangles, respectively related to the accumulation of amyloid beta peptide (Aß) in brain tissues and changes in the cytoskeleton that originate from hyperphosphorylation of the Tau protein in neurons. Some lines of evidence support the hypothesis that oxidative, nitrosative stress and inflammation play an important role in the pathogenesis of both AD and MCI. Selenium, an essential mineral to humans, is incorporated into the active site of 25 selenoproteins, of which at least one third has an antioxidant role, in addition to its potential in modulating the inflammatory system. Therefore, the appropriate nutritional status related to selenium seems to exert a neuroprotective effect, reducing the risk for MCI and AD and decreasing the progression of these diseases. Selenium is delivered to the brain by the interaction of selenoprotein P (SELENOP) with the ApoE2 receptor (ApoER2). Apolipoprotein E (ApoE) also interacts with ApoER2 in lipid metabolism. Thus, it can be speculated that individuals that carry apolipoprotein E ε4 gene (APOE ε4), the main genetic polymorphism that increases the risk of AD, may have impaired selenium delivery to the brain since ApoER2 receptors of the APOE ε4 carriers are sequestered to intracellular compartments, being less expressed in the plasma membrane decreasing its interaction with SELENOP. This study aimed to assess whether the distribution of selenium in the plasma and CSF of subjects with MCI and AD is affected by the APOE ε4 allele, evaluate whether the nutritional status of selenium affects biological signature markers for AD (amyloid beta peptide, tau protein and phosphorylated tau protein) and to asses the concentrations of inflammatory cytokines. For this purpose, plasma and cerebrospinal fluid (CSF) samples were selected from the biological material bank of the Institute of Psychiatry of FMUSP, with 14 subjects from the MCI group, 28 from the DA group and 28 from control subjects, both genders, aged over 60 years and São Paulo residents. The following markers were evaluated: selenium concentrations in plasma and CSF, SELENOP concentrations in plasma and CSF, inflammatory cytokines, brain-derived neurotrophic factor (BDNF) and biological signature for AD. There was no difference between the three different groups in relation to selenium and SELENOP; in addition, there was no influence of the APOE ε4 genotype on selenium and SELENOP concentrations, but there was a tendency towards lower plasma selenium concentrations in the APOE ε4 carriers. There was also a tendency for lower scores on the MMSE and CAMCOG tests in subjects with lower plasma selenium concentrations. It was not shown that selenium nutritional status influences the concentrations of biological signature for AD and inflammatory cytokines, with the exception of IL-10 which showed a positive correlation with plasma SELENOP. From these results, we concluded that selenium nutritional status does not seem to have a significant influence in aspects of MCI and DA and that its distribution is not altered by the APOE genotype ε4

Safety, Tolerability, Pharmacokinetics, and Food Effects on TAC-302 in Healthy Participants: Randomized, Double-Blind, Placebo-Controlled, Single-Dose and Multiple-Dose Studies.

TAC-302 stimulates neurite outgrowth activity and is expected to restore urinary function in patients with lower urinary tract dysfunction. We conducted 2 phase 1, randomized, placebo-controlled studies to confirm the safety and pharmacokinetics (PK) of TAC-302 in healthy adult Japanese male volunteers. In the first-in-human single-dose study (n = 60), TAC-302 was administered at doses from 100 to 1200 mg after an overnight fast. The effects of a meal on the PK of TAC-302 400 mg were also examined. A multiple-dose study (n = 36) evaluated the effects of meal fat content on the PK of single doses of TAC-302 (100, 200, or 400 mg) and multiple doses of TAC-302 administered for 5 days (100, 200, and 400 mg twice daily). TAC-302 showed linear PK up to doses of 1200 mg in the fasting state, and across the dose range of 100-400 mg in the fed state. No accumulation of TAC-302 was observed. Food, particularly with high fat content, increased TAC-302 plasma concentrations. No differences were observed in the adverse event incidence between the TAC-302 and placebo groups in either study. TAC-302 showed a wide safety margin.

Effect of recombinant human nerve growth factor eye drops in patients with dry eye: a phase IIa, open label, multiple-dose study.

BACKGROUND: Dry eye disease (DED) affects more than 14% of the elderly population causing decrease of quality of life, high costs and vision impairment. Current treatments for DED aim at lubricating and controlling inflammation of the ocular surface. Development of novel therapies targeting different pathogenic mechanisms is sought-after. The aim of this study is to evaluate safety and efficacy of recombinant human nerve growth factor (rhNGF) eye drops in patients with DED. METHODS: Forty consecutive patients with moderate to severe DED were included in a phase IIa, prospective, open label, multiple-dose, clinical trial to receive rhNGF eye drops at 20 µg/mL (Group 1: G1) or at 4 µg/mL (Group 2: G2) concentrations, two times a day in both eyes for 28 days (NCT02101281). The primary outcomes measures were treatment-emerged adverse events (AE), Symptoms Assessment in Dry Eye (SANDE) scale, ocular surface staining and Schirmer test. RESULTS: Of 40 included patients, 39 completed the trial. Both tested rhNGF eye drop concentrations were safe and well tolerated. Twenty-nine patients experienced at least one AE (14 in G1 and 15 in G2), of which 11 had at least 1 related AE (8 in G1 and 3 in G2). Both frequency and severity of DED symptoms and ocular surface damage showed significant improvement in both groups, while tear function improved only in G1. CONCLUSIONS: The data of this study indicate that rhNGF eye drops in both doses is safe and effective in improving symptoms and signs of DED. Randomised clinical trials are ongoing to confirm the therapeutic benefit of rhNGF in DED. TRIAL REGISTRATION NUMBER: NCT02101281.

Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans.

Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising.

Neurotrophins: Role in adverse pregnancy outcome.

Proper placental development is essential during pregnancy since it forms the interface between the maternal-foetal circulations and is critical for foetal nutrition and oxygenation. Neurotrophins such as nerve growth factor (NGF), brain derived neurotrophin (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5) are naturally occurring molecules that regulate development of the placenta and brain. BDNF and NGF also involved in the regulation of angiogenesis. Recent studies suggest that the levels of BDNF and NGF are regulated by docosahexaenoic acid (DHA) which is an important omega-3 fatty acid and is a structural component of the plasma membrane. Oxidative stress during pregnancy may lower the levels of DHA and affecting the fluidity of the membranes leading to the changes in the levels and expression of BDNF and NGF. Therefore altered levels and expression of NGF and BDNF may lead to abnormal foetal growth and brain development that may increase the risk for cardiovascular disease, metabolic syndromes and neurodevelopmental disorders in children born preterm. This review discuss about the neurotrophins and their role in the feto-placental unit during critical period of pregnancy.

The neuroimmune guidance cue netrin-1: a new therapeutic target in cardiovascular disease.

Netrins are a family of proteins involved in cell migration and axon guidance during embryogenesis. The different functions and mechanisms of action of this family of proteins have been better characterized with the study of netrin-1. They are chemotropic and act as a bifunctional regulator of neuron migration. Apart from its role in the central nervous system, researchers have proven that netrin-1 plays a role in the development and formation of non-neural tissue; netrin-1 is thereby involved in regulation of cancers, cardiovascular diseases, kidney diseases, and other diseases. Concerning the cardiovascular realm, netrin-1 promotes angiogenesis and accelerates atherosclerosis, protects the heart against ischemia-reperfusion injury, and reduces the infarct size. These findings make the neuroimmune guidance cue netrin-1 an important therapeutic target. This work seeks to review the subject based on studies that have been conducted over the past decade to identify the perspectives and extent of the research on this protein in the field of cardiology.

Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial.

BACKGROUND AND OBJECTIVES: Nerve growth factor (NGF) is a neurotrophin with therapeutic possibilities that extend from the nervous system to the eye. We tested the safety, maximal tolerated dose, pharmacokinetics, and antigenicity of a novel human recombinant NGF (rhNGF) eye-drop formulation in a phase I study. METHODS: This prospective, randomized, double-masked, vehicle-controlled trial, sponsored by Dompé SpA (registered as NCT01744704 at ClinicalTrials.gov), enrolled 74 healthy volunteers (24 females, 50 males, age 40.2 ± 11.8 years). Subjects were randomized in three cohorts to receive (1) a single eye-drop containing 0.0175, 0.175, or 0.7 µg rhNGF; (2) a single ascending dose of rhNGF eye drops three times a day for 1 day (total daily dose 2.1, 6.3, or 18.9 µg), or vehicle; or (3) a multiple ascending dose of rhNGF eye drops three times a day for 5 days (total dose 10.5, 31.5, or 94.5 µg), or vehicle. Outcome measures included blood chemistry, urinalyses, vital signs, electrocardiograms (ECGs), serum NGF antibodies, ocular and systemic adverse events (AEs), visual acuity, tear function, intraocular pressure, fundus oculi, and ocular symptoms. RESULTS: Administration of rhNGF eye drops did not result in a significant increase of circulating NGF levels and no antidrug antibodies were detected in serum. No serious AEs were recorded, and a few mild, transient ocular AEs related to rhNGF administration were reported only at the highest concentration. CONCLUSIONS: rhNGF eye drops were well tolerated, with no detectable clinical evidence of systemic AEs. These results pave the way for the development of clinical trials on rhNGF in ophthalmology.

Neurofascin 186 specific autoantibodies induce axonal injury and exacerbate disease severity in experimental autoimmune encephalomyelitis.

Axonal injury is considered the major cause of chronic disability in multiple sclerosis (MS) patients, however the mechanisms behind remain still unclear. Recently, it was demonstrated that autoantibodies against Neurofascin, a cell adhesion molecule within the adult nervous system, can contribute to the development of axonal pathology in some patients. We compared the ability of the two different isoforms of Neurofascin, Nfasc155 and Nfasc186, to induce a pathogenic antibody response in the Dark Agouti (DA) rat. Animals were immunized with recombinant proteins prior to induction of experimental autoimmune encephalomyelitis (EAE) by adoptive transfer of activated MOG-specific T cells. Only Nfasc186 induced an axopathic autoantibody response in vivo, despite extensive cross reactivity between the two isoforms as shown by ELISA and flow cytometry. In this case, using transfected cell lines failed to differentiate between pathogenic and non-pathogenic responses. These findings have important implications with respect to the usage of cell based assays as an approach to detect pathologically relevant autoantibodies in clinical samples.

Intranasal administration: a potential solution for cross-BBB delivering neurotrophic factors.

Neurotrophic factors (NTFs) are endogenous polypeptides that regulate the growth, survival, differentiation, and functioning of neurons. The neuroprotective effects of NTFs in experimental animals give strong rationale for developing therapies for neurological disorders. However, when NTFs are applied in clinical trials, great expectation leads to equal disappointment. NTFs are large molecular-weighted and hydrophilic proteins, which limits their access to the central nervous system (CNS) after systemic administration, principally due to poor blood-brain barrier (BBB) permeability and unfavorable pharmacokinetic profiles. Although intracerebral infusion may transport NTFs into the CNS, the invasiveness limits its clinical application. Intranasal administration has been under research for decades and presents promising outcomes in preclinical studies for brain delivering of NTFs. After intranasal delivery, NTFs gain direct and quick access into the CNS at concentrations high enough to elicit their biological effects, bypassing the BBB and minimizing systemic exposure. Due to its invasiveness and convenience, intranasal delivery is feasible for NTFs administration. Although direct evidence of nose-to-brain pathway in human is lacking due to ethical problems, the existence of the nose-to-cerebral spinal fluid pathway has been verified in men. Furthermore, there is abundant indirect evidence for the nose-to-brain pathway as determined by the efficacy of intranasally administered neuroproteins, such as insulin, oxytocin, and vasopressin in clinical trials. Based on the solid preclinical research supporting the efficacy of intranasal NTFs, and the successful clinical application of neuroproteins (not NTFs), it is time to evaluate clinical application of NTFs in treating both acute and chronic CNS diseases.

Growth factors and neuropathic pain.

A treatment for neuropathic pain is an important unmet medical need because this pain often is refractory to many medical interventions. An important element in the development of neuropathic pain is a dysfunction in the activity of peripheral nerves. Because neurotrophic factors affect nerve development and maintenance, modulating the activity of these factors can alter neuronal pathophysiology and produce a disease-modifying effect. Blocking the activity of nerve growth factor or enhancing the activity of either glial-derived neurotrophic factor or artemin has shown potential for normalizing neuronal activity and attenuating signs of neuropathic pain in animal models and clinical studies. This article discusses the role of these factors in neuropathic pain and the implications for the development of novel therapeutics.

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.

Neurotrophic factors as a therapeutic target for Parkinson's disease.

BACKGROUND: The search for therapeutic agents that might alter the disease course in Parkinson's disease (PD) is ongoing. One area of particular interest involves neurotrophic factors (NTFs), with those of the glial cell line-derived neurotrophic factor (GDNF) family showing greatest promise. The safety and efficacy of these therapies has recently come into question. Furthermore, many of the key questions pertaining to such therapies, such as the optimal method of delivery, timing of treatment and selection of patients most likely to benefit, remain unanswered. OBJECTIVE: In this review we sought to evaluate the therapeutic potential of NTFs in the treatment of PD. We appraised the evidence provided by both in vitro and in vivo work before proceeding to a critical assessment of the relevant clinical trial data. METHODS: Relevant literature was identified using a PubMed search of articles published up to October 2007. Search terms included: 'Parkinson's disease', 'Neurotrophic factors', 'BDNF' (Brain-derived neurotrophic factor), 'GDNF' and 'Neurturin'. Original articles were reviewed, and relevant citations from these articles were also appraised. CONCLUSION: NTF therapy has potential in the treatment of nigrostriatal dysfunction in PD but numerous methodological and safety issues will need to be addressed before this approach can be widely adopted. Furthermore PD is now recognized as being more than a pure motor disorder, and one in which neuronal loss is not just confined to the dopaminergic nigrostriatal system. Non-motor symptomatology in PD is unlikely to benefit from therapies that target only the nigrostriatal system, and this must inform our thinking as to the maximal achievable benefit that NTFs are ever likely to provide.

Angels and demons: neurotrophic factors and epilepsy.

Several lines of evidence indicate that neurotrophic factors (NTFs) could be key causal mediators in the development of acquired epileptic syndromes. Yet the trophic properties of NTFs indicate that they might be used to treat epilepsy-associated damage. Accordingly, different NTFs, or even the same NTF, could produce functionally contrasting effects in the context of epilepsy. Recent experimental evidence begins to shed light on the mechanisms underlying these contrasting effects. Understanding these mechanisms will be instrumental for the development of effective therapies, which must be based on a careful consideration of the biological properties of NTFs. Here, we critically evaluate new information emerging in this area and discuss its implications for clinical treatment.

Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study.

We have shown previously that intraparenchymal infusion of glial cell line-derived neurotrophic factor (GDNF) continuously into the posterior putamen in five Parkinson's disease patients is safe and may represent a new treatment option. Here, we report a continuation of this phase I study. After 2 years of continual GDNF infusion, there were no serious clinical side effects and no significant detrimental effects on cognition. Patients showed a 57% and 63% improvement in their off-medication motor and activities of daily living subscores of the Unified Parkinson's Disease Rating Scale, respectively, and health-related quality-of-life measures (Parkinson's Disease Questionnaire-39 and Short Form-36) showed general improvement over time.