davunetide and Neurodegenerative-Diseases

This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in the laboratory of Prof. Illana Gozes. The effects of NAP and its related peptides in models of neurodegenerative diseases and other neurological disorders will be described here in details. Possible mechanisms of NAP actions include anti-inflammatory effect, antioxidant activity, inhibition of protein aggregation and interaction with microtubules. In line with the fact that all of these features are characteristic to most neurological/neurodegenerative disorders, NAP was found to have beneficial effects on the behavioral manifestations associated with these disorders.

Topics: Animals; Humans; Hypoxia; Learning; Neurodegenerative Diseases; Oligopeptides; Retina

Davunetide is the first neuroprotective peptide in its class, and has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties. Davunetide has also been shown to prevent apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization. Potential clinical uses of davunetide include neurodegenerative disorders such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) or cognitive impairment in other diseases such as schizophrenia where microtubule structure and function is known to be impaired. The nonclinical and clinical safety of davunetide is reviewed here in detail. Pre-clinical toxicology studies in rats and dogs using the maximum feasible dose of davunetide provide strong evidence that davunetide is well-tolerated. Similarly, data from 10 separate clinical trials of davunetide, investigating safety and efficacy provide evidence that davunetide is generally safe and well-tolerated, and has shown some signs of clinical efficacy.

Topics: Animals; Apoptosis; Clinical Trials as Topic; Dose-Response Relationship, Drug; Humans; Microtubules; Neurodegenerative Diseases; Neuroprotective Agents; Oligopeptides; Toxicity Tests; Treatment Outcome

This review focuses on the therapeutic effects and mechanisms of action of NAP (davunetide), an eight amino acid snippet derived from activity-dependent neuroprotective protein (ADNP) which was discovered in our laboratory. We have recently described the effects of NAP in neurodegenerative disorders, and we now review the beneficial effects of NAP and other microtubule-stabilizing agents on impairments in axonal transport. Experiments in animal models of microtubule-deficiency including tauopathy (spanning from drosophila to mammals) showed protection of axonal transport by microtubule-stabilizers and NAP, which was coupled to motor and cognitive protection. Clinical trials with NAP (davunetide) are reviewed paving the path to future developments.

Topics: Animals; Antineoplastic Agents; Axonal Transport; Brain; Clinical Trials as Topic; Humans; Mice; Microtubules; Molecular Targeted Therapy; Neurodegenerative Diseases; Neuroprotective Agents; Oligopeptides; Rats; tau Proteins; Tauopathies; Tubulin Modulators

Accelerated neuronal death brings about cognitive as well as motor and other dysfunctions. A major neuropeptide, vasoactive intestinal peptide (VIP), has been shown to be neuroprotective. However, VIP-based drug design is hampered by the instability of the peptide and its limited bioavailability. Two independent approaches were thus taken to exploit VIP as a lead drug candidate: (1) Potent neuroprotective lipophilic analogs of VIP were synthesized, e.g. [stearyl-norleucine-17] VIP (SNV); and (2) potent neuroprotective peptide derivatives were identified that mimic the activity of VIP-responsive neuroprotective glial proteins. VIP provides neuronal defense by inducing the synthesis and secretion of neuroprotective proteins from astrocytes; activity-dependent neuroprotective protein (ADNP) was discovered as such glial cell mediator of VIP- and SNV-induced neuroprotection. In subsequent studies, an eight-amino-acid peptide, NAP, was identified as the smallest active element of ADNP exhibiting potent neuroprotective activities. This paper summarizes the biological effects of SNV and NAP and further reports advances in NAP studies toward clinical development. An original finding described here shows that NAP, while protecting neurons, demonstrated no apparent effect on cell division in a multiplicity of cell lines, strengthening the notion that NAP is a specific neuroprotective drug candidate.

Topics: Animals; Astrocytes; Cell Division; COS Cells; Homeodomain Proteins; Humans; Mice; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroprotective Agents; NIH 3T3 Cells; Oligopeptides; PC12 Cells; Rats; Vasoactive Intestinal Peptide

NAP (davunetide) is a novel neuroprotective compound with mechanism of action that appears to involve microtubule (MT) stabilization and repair. To evaluate, for the first time, the impact of NAP on axonal transport in vivo and to translate it to neuroprotection in a severe neurodegeneration, the SOD1-G93A mouse model for amyotrophic lateral sclerosis (ALS) was used. Manganese-enhanced magnetic resonance imaging (MRI), estimating axonal transport rates, revealed a significant reduction of the anterograde axonal transport in the ALS mice compared to healthy control mice. Acute NAP treatment normalized axonal transport rates in these ALS mice. Tau hyperphosphorylation, associated with MT dysfunction and defective axonal transport, was discovered in the brains of the ALS mice and was significantly reduced by chronic NAP treatment. Furthermore, in healthy wild type (WT) mice, NAP reversed axonal transport disruption by colchicine, suggesting drug-dependent protection against axonal transport impairment through stabilization of the neuronal MT network. Histochemical analysis showed that chronic NAP treatment significantly protected spinal cord motor neurons against ALS-like pathology. Sequential MRI measurements, correlating brain structure with ALS disease progression, revealed a significant damage to the ventral tegmental area (VTA), indicative of impairments to the dopaminergic pathways relative to healthy controls. Chronic daily NAP treatment of the SOD1-G93A mice, initiated close to disease onset, delayed degeneration of the trigeminal, facial and hypoglossal motor nuclei as was significantly apparent at days 90-100 and further protected the VTA throughout life. Importantly, protection of the VTA was significantly correlated with longevity and overall, NAP treatment significantly prolonged life span in the ALS mice.

Topics: Amyotrophic Lateral Sclerosis; Animals; Axonal Transport; Blotting, Western; Body Weight; Brain; Contrast Media; Disease Progression; Female; Magnetic Resonance Imaging; Male; Manganese; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neuroprotective Agents; Oligopeptides; Phosphorylation; Psychomotor Performance; Spinal Cord; tau Proteins; Tubulin; Tyrosine; Ventral Tegmental Area

NAP (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln, single letter code: NAPVSIPQ) and ADNF-9 (activity-dependent neurotrophic factor-9; Ser-Ala-Leu-Leu-Arg-Ser-Ile-Pro-Ala; single letter code: SALLRSIPA) are peptides derived from naturally occurring glial proteins that have shown neuroprotection in rodent model systems. Here, the neuroprotective activity of ADNF-9 and NAP was tested in two human models of neuronal degeneration in culture mediated by oxidative stress: normal human cortical neurons treated with H2O2 and Down's syndrome (DS) cortical neurons. Incubation of normal cortical neurons with 50 microM H2O2 for 1 hour resulted in morphological and structural changes consistent with neuronal degeneration and loss of viability of more than 60% of the neurons present in the culture. Addition of ADNF-9 or NAP at femtomolar concentrations resulted in significant increases in survival of normal neurons treated with H2O2. Femtomolar concentrations of ADNF-9 or NAP exhibited a similar neuroprotective efficacy, comparable to the antioxidant N-tert-butyl-2-sulpho-phenylnitrone at 100 microM (s-PBN). Treatment of DS cortical neurons with ADNF-9 or NAP resulted in a significant increase in neuronal survival as well as reduction of degenerative morphological changes. The results suggest that ADNF-9 and NAP possess potent neuroprotective properties against oxidative damage in human neurons that may be useful to preserve neuronal function and prevent neuronal death associated with chronic neurodegenerative disorders.

Topics: Animals; Apoptosis; Cell Survival; Cells, Cultured; Cerebral Cortex; Down Syndrome; Fetus; Humans; Mice; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Oligopeptides; Oxidative Stress

Oxidative stress is a common associative mechanism that is part of the pathogenesis of many neurodegenerative diseases. Vasoactive intestinal peptide (VIP) is a principal neuropeptide associated with normal development and aging. We have previously reported that VIP induced the secretion of proteins from glial cells, including the novel survival-promoter: activity-dependent neurotrophic factor (ADNF). ADNF-9, a nine amino acid peptide derived from ADNF, protects neurons from death caused by various toxins. In the present study, we examined the neuroprotective effect of VIP against oxidative stress in a pheochromocytoma cell line (PC12). In addition, a lipophilic derivative of VIP, Stearyl-Nle17-VIP (SNV), and two femtomolar-acting peptides: ADNF-9 and a 70% homologous peptide to ADNF-9, NAP were tested as well. PC12 cells were treated with 100 microM H2O2 for 24 h resulting in a reduction in cell survival to 35-50% as compared to controls. Addition of VIP or SNV prior and during the exposure to100 microM H2O2 increased cell survival to 80-90% of control values. Culture treatment with ADNF-9 or NAP in the presence of 100 microM H2O2 increased cell survival to 75-80% of control values. Messenger RNA expression analysis revealed that incubation with VIP resulted in a twofold increase in VIP mRNA, whereas NAP treatment did not cause any change in VIP expression, implicating different mechanisms of action. Furthermore, addition of an ADNF-9 antibody prevented the ability of VIP to protect against oxidative stress, suggesting that VIP protection is partially mediated via an ADNF-like protein.

Topics: Animals; Antibodies; Antibody Specificity; Cell Survival; Gene Expression; Hydrogen Peroxide; Nerve Tissue Proteins; Neurodegenerative Diseases; Neuroprotective Agents; Oligopeptides; Oxidative Stress; PC12 Cells; Rats; Vasoactive Intestinal Peptide