Cilostazol, a Phosphodiesterase 3 Inhibitor, Moderately Attenuates Behaviors Depending on Sex in the Ts65Dn Mouse Model of Down Syndrome

Abstract

People with Down syndrome, which is a trisomy of chromosome 21, exhibit intellectual disability from infancy and neuropathology similar to Alzheimer's disease, such as amyloid plaques, from an early age. Recently, we showed that cilostazol, a selective inhibitor of phosphodiesterase (PDE) 3, promotes the clearance of amyloid β and rescues cognitive deficits in a mouse model of Alzheimer's disease. The objective of the present study was to examine whether cilostazol improves behaviors in the most widely used animal model of Down syndrome, i.e., Ts65Dn mice. Mice were supplemented with cilostazol from the fetal period until young adulthood. Supplementation significantly ameliorated novel-object recognition in Ts65Dn females and partially ameliorated sensorimotor function as determined by the rotarod test in Ts65Dn females and hyperactive locomotion in Ts65Dn males. Cilostazol supplementation significantly shortened swimming distance in Ts65Dn males in the Morris water maze test, suggesting that the drug improved cognitive function, although it did not shorten swimming duration, which was due to decreased swimming speed. Thus, this study suggests that early supplementation with cilostazol partially rescues behavioral abnormalities seen in Down syndrome and indicates that the effects are sex-dependent.

Prenatal, but not Postnatal, Curcumin Administration Rescues Neuromorphological and Cognitive Alterations in Ts65Dn Down Syndrome Mice

“…The few studies that have assessed TS mice phenotypes in both sexes separately show conflicting results. Some of them reported sex differences in cognition (83,84); however, consistent with our results, other studies did not find differences between them (85,86).…”

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

“…The inhibition of PDE10A has been proposed for FXS (even if no data have been published yet), ASD [105], and ADHD [106]. The inhibition of PDE3 has been used in DS and is potentially useful for ASD [113]. Indeed, this drug protects against cognitive impairment and white matter disintegration in a mouse model of chronic cerebral hypoperfusion [73], a phenotype characterizing some ASD patients [134].…”

“…Finally, the surprising results from Zamarbide et al (CC2D1A) and Tsuji et al (DS) suggest the possibility that a sex-specific regulation (or deregulation) of cAMP or cGMP levels exists [ 113 , 125 ]. These findings are particularly important for the treatment of ASD and ID, since the ratio of incidence of this disorder is 3:2 in males vs. females, and this could result in a sex-specific treatment.…”

“…In a recent study, the administration of cilostazol (PDE3 inhibitor) to Ts65Dn mice from fetal to adult age ameliorated cognition and sensorimotor function in females. The same treatment in males improved their hyperactive locomotion and spatial memory [ 113 ]. Overall, these results seem to be consistent with the previous observation that cilostazol promotes the clearance of Aβ plaques and rescues cognitive deficits in a mouse model [ 113 ] of AD and reduces the cognitive decline in patients affected by AD [ 75 ].…”

“…The same treatment in males improved their hyperactive locomotion and spatial memory [ 113 ]. Overall, these results seem to be consistent with the previous observation that cilostazol promotes the clearance of Aβ plaques and rescues cognitive deficits in a mouse model [ 113 ] of AD and reduces the cognitive decline in patients affected by AD [ 75 ].…”