The microtubule interacting drug candidate NAP protects against kainic acid toxicity in a rat model of epilepsy

Zemlyak, Ilona; Manley, Nathan C.; Vulih-Shultzman, Inna; Cutler, Andrew J.; Graber, Kevin; Sapolsky, Robert M.; Gozes, Illana

doi:10.1111/j.1471-4159.2009.06415.x

Cited by 25 publications

(18 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, NP031112 prevents inflammation and neurodegeneration under excitotoxic conditions [154], similar to davunetide [155].…”

Section: Recent Historic Perspectivementioning

confidence: 96%

Tau Pathology and Future Therapeutics

Gozes

2010

CAR

View full text Add to dashboard Cite

The current review discusses microtubules and tau in the healthy brain and move on to the underling pathology of Alzheimer's disease (AD) with emphasis on tau and neurofibrillary tangles. Tangles have been associated with cognitive dysfunction causing neurodegeneration in the absence of plaques. AD, the most abundant tauopathy is characterized by β-amyloid plaques and tau tangles. An abundance of tau inclusions, in the absence of β-amyloid deposits, defines Pick's disease (frontotemporal lobar degeneration), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and other diseases. Our own focused research is on activity-dependent neuroprtective protein (ADNP). Our findings show that ADNP-deficiency leads to tauopathy which is inhibited by the ADNP derived drug candidate, davunetide (originally known as NAP). The current review further describes tau as a potential diagnostic marker followed by drug candidates that are aimed at fighting tau pathology. A recent historical perspective is the final comment of the manuscript. This paper is not a comprehensive review of the literature rather it gives my own point of view in the face of many publications and a great unmet need for future therapeutics. It is hoped that davunetide, a most advanced drug in clinical development will rapidly advance as a first effective treatment for a number of brain disorders broadly categorized as frontotemporal dementia (FTD) and serve as a prototype for future therapeutic development toward modification and remedy of currently intractable neurodegenerative diseases.

show abstract

“…Thus, NP031112 prevents inflammation and neurodegeneration under excitotoxic conditions [154], similar to davunetide [155].…”

Section: Recent Historic Perspectivementioning

confidence: 96%

Tau Pathology and Future Therapeutics

Gozes

2010

CAR

View full text Add to dashboard Cite

show abstract

“…For further reference on ADNP and NAP, please refer to our previous reviews with some examples cited here, [18,[45][46][47][48][49][50] and to our recent studies extending ADNP biology and NAP efficacy to other neurotrophic and neurodegenerative disease models [50][51][52][53][54][55][56][57][58][59][60].…”

Section: Introductionmentioning

confidence: 98%

Protection Against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects

Shiryaev¹,

Pikman²,

Giladi³

et al. 2011

CPD

Self Cite

View full text Add to dashboard Cite

Activity-dependent neuroprotective protein (ADNP) is essential for brain formation and partial deficiency in ADNP results in cognitive deficits coupled with tauopathy and neuronal cell death. Our previous results indicated that a peptide snippet from ADNP, NAPVSIPQ (NAP, generic name, davunetide) can restore in part ADNP deficiencies. NAP interacts with tubulin and this interaction is displaced by the NAP related peptide that is derived from activity-dependent neurotrophic factor (ADNF), SALLRSIPA (SAL) and its all D-amino acid peptide derivative (D-SAL, also known as AL-309). Both NAP and D-SAL were shown to protect neurons against amyloid beta toxicity however the mechanism of protection is still under investigation. In addition, NAP protects against tau hyperphosphorylation associated with ADNP deficiency, in vivo. To investigate whether the mechanism of in vitro neuroprotection relates to the in vivo protection against tauopathy and to draw potential additional parallelism between NAP and D-SAL, we asked if: 1]NAP and D-SAL protect against amyloid beta related tau hyperphosphorylation in vitro; and 2] D-SAL protects against haploinsufficiency in ADNP, inhibiting tauopathy in vivo. Assessment of NAP and D-SAL neuroprotection in primary cortical neuro-glial cultures treated with amyloid beta showed that both peptides reduced toxin-related neuronal damage and protected against tau hyperphosphorylation. In vivo, chronic D-SAL administration protected against tau hyperphosphorylation associated with ADNP deficiency (ADNP+/- mice), showing for the first time protection against deficits in odor discrimination and in social recognition. These studies associate neuroprotection in vivo and in vitro and provide a broad base for future drug development based on NAP and D-SAL against multiple neurodegenerative conditions.

show abstract

“…An early study demonstrated the protective role of microtubule stabilization with taxol on hippocampal neurons exposed to kainic acid, [42]. Similarly the microtubule stabilizing agent davunetide protects against kainic acid excitotoxicity in hippocampal cells both in vitro and in vivo [43]. However in these studies taxol was globally applied to neurons and protection attributed to prevention of calcium influx through calcium permeable AMPA receptors [42].…”

Section: Discussionmentioning

confidence: 99%

Excitotoxin-induced caspase-3 activation and microtubule disintegration in axons is inhibited by taxol

King

Southam

Dittmann

et al. 2013

acta neuropathol commun

View full text Add to dashboard Cite

BackgroundAxon degeneration, a key pathological event in many neurodegenerative diseases and injury, can be induced by somatodendritic excitotoxin exposure. It is currently unclear, however, whether excitotoxin-induced axon degeneration is mechanistically similar to Wallerian degeneration, which occurs following axon transection, but does not involve axonal caspase activation.ResultsWe have used mouse primary cortical neurons at 9 days in vitro, in a compartmented culture model that allows separation of the axon from the soma, to examine the pathological cascade of excitotoxin-induced axon degeneration. Excitotoxicity induced by chronic exposure to kainic acid, resulted in axonal fragmentation, which was associated with activation of caspase-3 in the axonal compartment. To examine the role of microtubules in these events, the microtubule-stabilizing agent, taxol, was added to either the axonal or somatodendritic compartment. Our results demonstrated that microtubule stabilization of axons resulted in a significant reduction in the number of fragmented axons following excitotoxin exposure. Interestingly, taxol exposure to either the somatodendritic or axonal compartment resulted in reduced caspase-3 activation in axons, suggesting that caspase activation is a downstream event of microtubule destabilization and involves signalling from the cell soma.ConclusionThese data suggest that excitotoxin-induced axon degeneration shows some mechanistic differences to Wallerian degeneration, and that microtubule stabilization may assist in protecting nerve cells from excitotoxic effects.

show abstract

The microtubule interacting drug candidate NAP protects against kainic acid toxicity in a rat model of epilepsy

Cited by 25 publications

References 47 publications

Tau Pathology and Future Therapeutics

Tau Pathology and Future Therapeutics

Protection Against Tauopathy by the Drug Candidates NAP (Davunetide) and D-SAL: Biochemical, Cellular and Behavioral Aspects

Excitotoxin-induced caspase-3 activation and microtubule disintegration in axons is inhibited by taxol

Contact Info

Product

Resources

About