Long-term cilostazol administration ameliorates memory decline in senescence-accelerated mouse prone 8 (SAMP8) through a dual effect on cAMP and blood-brain barrier

Neuropharmacology. 2017 Apr;116:247-259. doi: 10.1016/j.neuropharm.2016.12.006. Epub 2016 Dec 12.

Abstract

Phosphodiesterases (PDEs), which hydrolyze and inactivate 3', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP), play an important role in synaptic plasticity that underlies memory. Recently, several PDE inhibitors were assessed for their possible therapeutic efficacy in treating cognitive disorders. Here, we examined how cilostazol, a selective PDE3 inhibitor, affects brain functions in senescence-accelerated mouse prone 8 (SAMP8), an animal model of age-related cognitive impairment. Long-term administration of cilostazol restored the impaired context-dependent conditioned fear memory of SAMP8 to match that in normal aging control substrain SAMR1. Cilostazol also increased the number of cells containing phosphorylated cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway. Finally, cilostazol improves blood-brain barrier (BBB) integrity, demonstrated by reduced extravasation of 2-deoxy-2-18F-fluoro-d-glucose and Evans Blue dye in the brains of SAMP8. This improvement in BBB integrity was associated with an increased amount of zona occludens protein 1 (ZO-1) and occludin proteins, components of tight junctions integral to the BBB. The results suggest that long-term administration of cilostazol exerts its beneficial effects on age-related cognitive impairment through a dual mechanism: by enhancing the cAMP system in the brain and by maintaining or improving BBB integrity.

Keywords: (18)F-FDG PET; BBB; CREB phosphorylation; Cilostazol; Memory; Senescence-accelerated mouse (SAM); cilostazol (PubChem ID: 2754).

MeSH terms

  • Aging / drug effects*
  • Aging / metabolism
  • Aging / pathology
  • Aging / psychology
  • Amygdala / diagnostic imaging
  • Amygdala / drug effects
  • Amygdala / metabolism
  • Amygdala / pathology
  • Animals
  • Blood-Brain Barrier / diagnostic imaging
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / metabolism
  • Blood-Brain Barrier / pathology
  • Capillary Permeability / drug effects
  • Capillary Permeability / physiology
  • Cilostazol
  • Conditioning, Classical / drug effects
  • Conditioning, Classical / physiology
  • Cyclic AMP / metabolism*
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Dentate Gyrus / diagnostic imaging
  • Dentate Gyrus / drug effects
  • Dentate Gyrus / metabolism
  • Dentate Gyrus / pathology
  • Disease Models, Animal
  • Fear / drug effects
  • Fear / physiology
  • Glucose / metabolism
  • Male
  • Memory Disorders / drug therapy*
  • Memory Disorders / etiology
  • Memory Disorders / metabolism
  • Memory Disorders / pathology
  • Nootropic Agents / blood
  • Nootropic Agents / pharmacokinetics
  • Nootropic Agents / pharmacology*
  • Phosphorylation / drug effects
  • Tetrazoles / blood
  • Tetrazoles / pharmacokinetics
  • Tetrazoles / pharmacology*
  • Tight Junctions / drug effects
  • Tight Junctions / metabolism
  • Time Factors
  • Zonula Occludens-1 Protein / metabolism

Substances

  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Nootropic Agents
  • Tetrazoles
  • Tjp1 protein, mouse
  • Zonula Occludens-1 Protein
  • Cyclic AMP
  • Glucose
  • Cilostazol