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Novel Object Recognition Test for the Investigation of Learning and Memory in Mice
Published on: August 30, 2017
Small molecule orexin agonist ROXA-47 enhances learning and memory in mice
Vijayakumar Mavanji1, Dehui Zhang2, Ann M Decker2
1Research Service, Veterans Affairs Health Care System, Minneapolis, MN, USA; Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
Pharmacology, Biochemistry, and Behavior
|July 30, 2026
Summary
New orexin agonists, ROXA-47 and YNT-185, improved cognitive function in aging mice. ROXA-47 primarily acts through the OX1R receptor, suggesting potential for treating age-related cognitive decline.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Aging impacts cognitive functions, sleep-wake cycles, and physical activity, partly regulated by lateral hypothalamic orexin neurons.
- Loss of orexin peptides and neurons is linked to aging and narcolepsy, conditions associated with cognitive impairment.
- Systemic administration of orexin agonists for cognitive enhancement has been limited by the lack of suitable small molecules.
Purpose of the Study:
- To develop a metabolically stable small molecule dual orexin receptor agonist (ROXA-47) for potential therapeutic use.
- To evaluate the cognitive effects of ROXA-47 and a selective OX2R agonist (YNT-185) via systemic administration in aging mice.
- To determine the specific orexin receptor (OX1R or OX2R) mediating the cognitive effects of ROXA-47.
Main Methods:
- Developed ROXA-47, a dual OX1R/OX2R agonist with low nanomolar potency.
- Administered ROXA-47 and YNT-185 peripherally to 6- and 12-month-old mice.
- Assessed cognitive function using the two-way active avoidance (TWAA) and contextual object recognition task (CORT).
- Utilized selective OX1R (SB-334867) and OX2R (JNJ-10397049) antagonists to probe ROXA-47's receptor specificity.
Main Results:
- Both ROXA-47 and YNT-185 improved performance in TWAA and CORT tasks in aging mice, indicating enhanced cognition.
- ROXA-47 treatment decreased latency and increased total responses in TWAA, and enhanced the discrimination index in CORT.
- The cognitive benefits of ROXA-47 were significantly reduced by the OX1R antagonist SB-334867, but not by the OX2R antagonist JNJ-10397049.
Conclusions:
- Systemic administration of small molecule orexin agonists like ROXA-47 can improve cognitive function in aging mice.
- ROXA-47 exerts its pro-cognitive effects predominantly through activation of the OX1R receptor.
- These findings highlight the therapeutic potential of OX1R-targeting orexin agonists for age-related cognitive decline.
