Resveratrol Reverses the Synaptic Plasticity Deficits in a Chronic Cerebral Hypoperfusion Rat Model

doi:10.1016/j.jstrokecerebrovasdis.2015.09.004

Journal of Stroke and Cerebrovascular Diseases

Volume 25, Issue 1, January 2016, Pages 122-128

https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.09.004 Get rights and content

Background

Dementia is the most prevalent neurological disease in aged people. Chronic cerebral hypoperfusion (CCH) is one of the causes of vascular dementia (VaD) and is also an etiological factor for Alzheimer's disease (AD). However, effective therapy for those two diseases is still missing. Resveratrol is a polyphenol produced by plants that have multiple biological functions, such as increased life span and delay in the onset of diseases associated with aging. It is known supplement with resveratrol could exert neuroprotection against multiple injury factors induced neuronal death and degeneration, as well as the cognitive decline of CCH rat model.

Methods

The morris water maze was used to evaluate the learning and memory, electrophysiological recording was used to detect the synaptic plasticity, the Golgi staining was used to examine the change of dendritic spines, the western blot was used to detect the proteins levels.

Results

We reported that resveratrol pretreatment effectively restore the synaptic plasticity in CCH rats both functional and structural. We also found that the PKA-CREB activation may be a major player in resveratrol-mediated neuroprotection in CCH model.

Conclusions

Our data provide the mechanistic evidence for the neuroprotective effects of resveratrol in vascular dementia.

Introduction

Vascular dementia (VaD) is another most common type of dementia after Alzheimer's disease in aged people.¹ It is reported that about 20% of dementia cases are diagnosed as VaD around the world.² Permanent occlusion of bilateral carotid arteries had been wildly used for the VaD model because of chronic cerebral hypoperfusion (CCH).³ Previous studies had reported that bilateral carotid arteries caused not only neuronal loss and neuronal inflammation in the cortex and hippocampus, but also impairments in learning and memory in rats.4, 5 It is known that synaptic plasticity is the molecular biological basis of learning and memory.⁶ Long-term potentiation (LTP) was recognized as a synaptic model of memory and was widely used as the parameter to evaluate the synaptic strength both in vivo and in vitro.⁷ Plenty of studies suggested that impaired synaptic plasticity plays an important role in the learning/memory deficits of VaD animal models.⁸ Thus, preservation of the ability of synaptic plasticity is a potential therapeutic strategy for the prevention of memory deficits in CCH.

Resveratrol (chemical name, 3,5,4′-trihydroxy-trans-stilbene) is a stilbenoid, a type of natural phenol, and a phytoalexin produced naturally by some plants in response to injury or when the plant is under attack by pathogens such as bacteria or fungi.⁹ The natural food sources of resveratrol include the skin of grapes, blueberries, raspberries, and mulberries.¹⁰ It is reported that resveratrol has multiple beneficial activities similar to those associated with caloric restriction, such as increased life span and delay in the onset of diseases associated with aging.¹¹ In the nervous system, the protective effects of resveratrol had also been well studied. For example, resveratrol prevents axonal degeneration after injury by enhancing Sir2 activity,¹² attenuates Aβ peptide-induced neuronal loss by activation of PKC in vitro,¹³ and rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons.¹⁴ Meanwhile, resveratrol ameliorates ischemia-induced neuronal cell death in a gerbil model with global cerebral ischemic injury,¹⁵ suggesting its protection from the brain injury induced by vascular factors. However, whether resveratrol could be protective to the synaptic plasticity of CCH rats model is not clear.

In this study, we found that preadministering resveratrol protects against impairments in spatial learning and memory in a CCH rats model. Resveratrol also prevents LTP inhibition and dendritic spine loss, as well as the synaptic proteins. The possible underlying mechanism for the prevention of resveratrol is through the activation of the protein kinase A (PKA) and cAMP-responsive element-binding protein (CREB) pathway.

Section snippets

Drugs and Antibodies

Resveratrol was purchased from Sigma-Aldrich (St. Louis, MO) and dissolved in dimethylsulfoxide. Polyclonal antibodies (pAbs) PKAα/β cαt against PKA catalytic α-subunit (1:1000) and PKA IIβ reg against PKA regulated β-subunit (1:1000), CREB against total CREB (1:1000), and phosphorylated CREB (p-CREB) against p-CREB at Ser133 site (1:1000) were purchased from Santa Cruz Biotechnology Inc. (Santa Cruz, CA). The pAb PSD95 (1:1000) against PSD95 protein, pAb PSD93 (1:1000) against PSD93 protein,

Resveratrol Protects against Impairments in Spatial Learning and Memory of CCH Rats

To investigate the effect of resveratrol to CCH-induced cognitive impairment, we first assessed spatial learning and memory abilities using the Morris water maze task. The results showed that the escape latency was decreased significantly during training (F[4, 12] = 15.9, P < .01) and there was a significant difference among the 4 groups (F[3, 12] = 18.43, P < .01). On the first 2 days, there was no significant difference among the groups. Beginning on day 3, the CCH group showed a longer

Discussion

The neuroprotective effects of resveratrol had been implicated in multiple aspects, such as reducing mitochondrial dysfunction, oxidative damage, and chronic inflammation; improving vascular function; and activating longevity genes including sirtuins. As resveratrol readily crosses the blood–brain barrier and its activity in the brain lasts for up to 4 hours,¹⁵ it had been used in healthy older persons to improve memory performance.²⁴ Meanwhile, resveratrol had also been used in the treatment

References (37)

NiJ. et al.
Progressive cognitive impairment following chronic cerebral hypoperfusion induced by permanent occlusion of bilateral carotid arteries in rats
Brain Res
(1994)
XiY. et al.
Neuronal damage, central cholinergic dysfunction and oxidative damage correlate with cognitive deficits in rats with chronic cerebral hypoperfusion
Neurobiol Learn Mem
(2014)
F. Cechetti et al.
Chronic brain hypoperfusion causes early glial activation and neuronal death, and subsequent long-term memory impairment
Brain Res Bull
(2012)
YangH.Y. et al.
Effects of repetitive transcranial magnetic stimulation on synaptic plasticity and apoptosis in vascular dementia rats
Behav Brain Res
(2015)
L. Fremont
Biological effects of resveratrol
Life Sci
(2000)
WangQ. et al.
Resveratrol protects against global cerebral ischemic injury in gerbils
Brain Res
(2002)
JinF. et al.
Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats
Eur J Pharmacol
(2008)
WangS.H. et al.
NGF promotes long-term memory formation by activating poly (ADP-ribose) polymerase-1
Neuropharmacology
(2012)
D.R. Friedland et al.
A modified Golgi staining protocol for use in the human brain stem and cerebellum
J Neurosci Methods
(2006)
L.L. Hurley et al.
Antidepressant effects of resveratrol in an animal model of depression
Behav Brain Res
(2014)

R. Bourtchuladze et al.

Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein

Cell

(1994)

M.R. Montminy et al.

Regulation of cAMP-inducible genes by CREB

Trends Neurosci

(1990)

T. Abel et al.

Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory

Cell

(1997)

L. Battistin et al.

Vascular cognitive disorder. A biological and clinical overview

Neurochem Res

(2010)

M.F. Dubois et al.

The incidence of vascular dementia in Canada: a comparison with Europe and East Asia

Neuroepidemiology

(2001)

A.J. Silva

Molecular and cellular cognitive studies of the role of synaptic plasticity in memory

J Neurobiol

(2003)

T.V. Bliss et al.

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

(1993)

M. Jasinski et al.

Resveratrol in prostate diseases—a short review

Cent European J Urol

(2013)

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: The authors declare no conflict of interest for this article.

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Resveratrol Reverses the Synaptic Plasticity Deficits in a Chronic Cerebral Hypoperfusion Rat Model

Background

Methods

Results

Conclusions

Introduction

Section snippets

Drugs and Antibodies

Resveratrol Protects against Impairments in Spatial Learning and Memory of CCH Rats

Discussion

Brain Res

Neurobiol Learn Mem

Brain Res Bull

Behav Brain Res

Life Sci

Brain Res

Eur J Pharmacol

Neuropharmacology

J Neurosci Methods

Behav Brain Res

Cell

Trends Neurosci

Cell

Vascular cognitive disorder. A biological and clinical overview

Neurochem Res

The incidence of vascular dementia in Canada: a comparison with Europe and East Asia

Neuroepidemiology

Molecular and cellular cognitive studies of the role of synaptic plasticity in memory

J Neurobiol

A synaptic model of memory: long-term potentiation in the hippocampus

Nature

Resveratrol in prostate diseases—a short review

Cent European J Urol