davunetide and Amyotrophic-Lateral-Sclerosis

Davunetide (NAP) is a leading drug candidate being tested against tauopathy. Davunetide is an eight-amino-acid peptide fragment derived by structure-activity studies from activity-dependent neuroprotective protein, activity-dependent neuroprotective protein (ADNP). ADNP is essential for brain formation. ADNP haploinsufficiency in mice results in tauopathy and cognitive deficits ameliorated by davunetide treatment. This article summarizes in brief recent reviews about NAP protection against tauopathy including the all D-amino acid analogue-D-NAP (AL-408). D-NAP was discovered to have similar neuroprotective functions to NAP in vitro. Here, D-NAP was tested as prophylactic as well as therapeutic treatment for amytrophic lateral sclerosis (ALS) in the widely used TgN(SOD1-G93A)1Gur transgenic mouse model. Results showed D-NAP-associated prophylactic protection, thus daily treatment starting from day 2 of age resulted in a prolonged life course in the D-NAP-treated mice, which was coupled to a significant decrease in tau hyperphosphorylation. These studies correlate protection against tau hyperphosphorylation and longevity in a severe model of ALS-like motor impairment and early mortality. NAP is a first-in-class drug candidate/investigation compound providing neuroprotection coupled to inhibition of tau pathology. D-NAP (AL-408) is a pipeline product.

Topics: Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Oligopeptides; Phosphorylation; Point Mutation; Protein Processing, Post-Translational; Recombinant Fusion Proteins; Superoxide Dismutase; Superoxide Dismutase-1; tau Proteins; Tauopathies

Topics: Amino Acid Motifs; Amyotrophic Lateral Sclerosis; Animals; Axonal Transport; Cell Line, Tumor; Disease Models, Animal; Dynamins; Endocytosis; Homeodomain Proteins; Hydrazones; Mice; Mice, Knockout; Microtubule-Associated Proteins; Microtubules; Nerve Tissue Proteins; Neurons; Neuroprotective Agents; Oligopeptides; Parkinsonian Disorders; Tauopathies

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