Activity-dependent neuroprotective protein (ADNP) derived peptide NAP prevents musculoskeletal abnormalities in ovariectomized mice.

Guz LS, Galushkin A, Gozes I

Frontiers in neuroscience28 Jul 2026

PMID42582414PMCIDPMC13457372DOI10.3389/fnins.2026.1891428PepBankPUB-42582414

Summary

Estrogen is an essential hormone that critically impacts bodily and brain functions, supporting learning, memory, and motor activities. A decrease in estrogen levels is associated with cognitive decline and motor dysfunction, such as muscle weakness. While conventional hormone replacement treatments (HRT) exist, those have limitations and potentially severe side effects. NAP (davunetide) is the smallest neuroprotective peptide site of activity-dependent neuroprotective protein (ADNP), a master regulator of cognition, essential for brain formation. It is known that NAP restores ADNP activity in cases of deficiency and it has already shown potential in preventing cognitive impairment, protecting against tauopathy, and improving motor function in various animal models and in clinical trials. Based on the dynamic regulation of ADNP by the estrous cycle and its involvement in steroidogenic pathways, we hypothesize that NAP may restore ADNP activity and thus serve as an alternative to conventional hormonal treatments. To test this hypothesis, 3-month-old female ICR mice underwent bilateral ovariectomy (OVX) or sham surgery and received daily intranasal administration of NAP, estrogen, or vehicle. Results showed a significant reduction in weight-normalized forelimb grip strength in the OVX model. Interestingly, grip strength was the only test that yielded significant OVX effects, and no significant differences were observed in the novel object recognition (NOR) test or computed tomography (CT) scans. Daily intranasal administration of either NAP or estrogen resulted in an apparent increase in the weight-normalized grip strength compared to the sham-treated OVX group. Furthermore, both the NAP- and the estrogen-treated OVX mouse groups did not statistically differ from the vehicle-treated sham control. These findings suggest that NAP may effectively prevent the loss of physical force production typically seen following ovarian hormone depletion, presenting a viable, non-hormonal candidate strategy for managing musculoskeletal symptoms. We hypothesize that the lack of significance OVX effects in other parameters was due to soy-derived phytoestrogens in the current Tel Aviv University's standard diet. Thus, the standard diet may have exerted a systemic estrogenic effect that masked the expected physiological phenotypes typically observed in OVX models. Future replication using phytoestrogen-deficient food is required to isolate the specific neuroprotective and musculoskeletal effects of NAP from dietary influence and clarify broader therapeutic benefits.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study2

2 results from studies that gave the peptide. No result from this study comes from people.

01AnimalAnimal study (in vivo)Efficacy outcome
In ovariectomized mice, daily intranasal NAP apparently increased weight-normalized grip strength compared with the sham-treated OVX group.
In plain wordsIn ovariectomized mice, daily nasal NAP apparently increased weight-adjusted grip strength compared with the sham-treated OVX group.
Peptide
Davunetide
Outcome
IncreaseWeight-normalized grip strength versus sham-treated OVX
Study
female ICR micen: not reported in source
ovariectomy
Comparator
Sham-treated OVX group
Outcome group
Exercise and physical function · Musculoskeletal
Studied dose
Dose not stated · intranasalAs given in this study (female ICR mice).
Source sentences
Summary
Daily intranasal administration of either NAP or estrogen resulted in an apparent increase in the weight-normalized grip strength compared to the sham-treated OVX group.
1 context sentence(design, population, supporting numbers)
Summary · context
To test this hypothesis, 3-month-old female ICR mice underwent bilateral ovariectomy (OVX) or sham surgery and received daily intranasal administration of NAP, estrogen, or vehicle.
Show in the study text Report a problemFND-4258241401
02AnimalAnimal study (in vivo)Efficacy outcome
In ovariectomized mice, the NAP-treated group did not statistically differ in grip strength from the vehicle-treated sham control.
In plain wordsIn ovariectomized mice, grip strength with NAP did not differ significantly from the vehicle-treated sham control.
Peptide
Davunetide
Outcome
No significant changeGrip strength versus vehicle-treated sham control
Study
female ICR micen: not reported in source
ovariectomy
Comparator
Vehicle-treated sham control
Outcome group
Exercise and physical function · Musculoskeletal
Studied dose
Dose not stated · intranasalAs given in this study (female ICR mice).
Source sentences
Summary
Furthermore, both the NAP- and the estrogen-treated OVX mouse groups did not statistically differ from the vehicle-treated sham control.
2 context sentences(design, population, supporting numbers)
Summary · context
Daily intranasal administration of either NAP or estrogen resulted in an apparent increase in the weight-normalized grip strength compared to the sham-treated OVX group.
Summary · context
To test this hypothesis, 3-month-old female ICR mice underwent bilateral ovariectomy (OVX) or sham surgery and received daily intranasal administration of NAP, estrogen, or vehicle.
Show in the study text Report a problemFND-4258241402

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Version history

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Version 2Current
27 Oct 2026, 18:20 UTC
Study results updated
Version 1
27 Oct 2026, 16:32 UTC
First added · source update from Europe PMC

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Terms as the source lists them.

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