The locus coeruleus neuroprotective drug vindeburnol normalizes behavior in the 5xFAD transgenic mouse model of Alzheimer’s disease

• Published in: Brain research 2019-01, Vol.1702, p.29-37
• Main Authors: Braun, David, Feinstein, Douglas L.
• Format: Article
• Language: English
• Subjects: Adrenergic Neurons - metabolism; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid; Amyloid beta-Protein Precursor - metabolism; Animals; Anxiety; BDNF; Brain - metabolism; Brain-Derived Neurotrophic Factor - metabolism; Disease Models, Animal; Disease Progression; Hippocampus - metabolism; Locus coeruleus; Locus Coeruleus - drug effects; Locus Coeruleus - metabolism; Locus Coeruleus - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Degeneration - pathology; Neurons - metabolism; Neuroprotective Agents - pharmacology; Noradrenaline; Norepinephrine - metabolism; Phosphodiesterase I - metabolism; Vincamine - analogs & derivatives; Vincamine - metabolism; Vincamine - pharmacology
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2017.12.028

•5xFAD transgenic mice show reduced anxiety-like behavior compared to wildtype littermates.•Vindeburnol, a derivative of the plant alkaloid vincamine, normalizes anxiety-like behavior.•Vindeburnol increases neuronal BDNF expression, dependent upon cAMP.•Vindeburnol inhibits phosphodiesterase type 1 activity.•Vindeburnol could provide benefit in neurological diseases involving damage to noradrenergic neurons. Damage to noradrenergic neurons in the Locus coeruleus (LC) occurs contributes to neuropathology and behavioral deficits in Alzheimer’s disease (AD); methods to reduce LC damage may therefore be of benefit. We previously showed that vindeburnol, a derivative of the plant alkaloid vincamine, reduced neuroinflammation, amyloid burden, and LC damage in a mouse model of AD; however, effects on behavior were not tested. We now tested the effects of vindeburnol on anxiety-like behavior in 5xFAD mice which develop robust amyloid burden at early ages. During novel object recognition testing, we observed that 5xFAD mice spent more time exploring than wildtype littermates, and that time was reduced by vindeburnol. Vindeburnol also reduced hyperlocomotion in the 5xFAD mice which may have contributed to their increased exploration times. In an open field test, vindeburnol normalized the increase of time spent in the center, and the decrease of time spent near the walls in 5xFAD mice. Vindeburnol reduced amyloid burden in the hippocampus and cortex, areas that contribute to regulation of anxiety-like behavior. In vitro, vindeburnol increased neuronal BDNF expression in a cAMP-dependent manner; and inhibited phosphodiesterase activity with an EC50 near 50 μM. These findings suggest that cAMP-mediated increases in neurotrophic factors contribute to beneficial effects of vindeburnol within the context of LC damage, which may be of value for treatment of some neuropsychiatric symptoms of AD.