In Vivo Cross-sectional Characterization of Cerebral Alterations Induced by Intracerebroventricular Administration of Streptozotocin

Audrey Kraska,Olène Dorieux,Philippe Hantraye,Marion Chaigneau,Mathieu D Santin,Marc Dhenain,Emmanuel Bourrin,Pierre Lestage,Fanny Petit,Nelly Joseph-Mathurin,Caroline Jan,Bernadette Allinquant

doi:10.1371/journal.pone.0046196

Abstract

Cerebral aging is often associated with the occurrence of neurodegenerative diseases leading to dementia. Animal models are critical to elucidate mechanisms associated to dementia and to evaluate neuroprotective drugs. Rats that received intracerebroventricular injection of streptozotocin (icv-STZ) have been reported as a model of dementia. In these animals, this drug induces oxidative stress and brain glucose metabolism impairments associated to insulin signal transduction failure. These mechanisms are reported to be involved in the pathogenesis of Alzheimer's disease and other dementia. Icv-STZ rats also display memory impairments. However, little is known about the precise location of the lesions induced by STZ administration. In this context, the present study characterized the cerebral lesions induced by two-doses of icv-STZ by using high-field magnetic resonance imaging to easily and longitudinally detect cerebral abnormalities and by using immunohistochemistry to evaluate neuronal loss and neuroinflammation (astrocytosis and microgliosis). We showed that, at high doses, icv-STZ induces severe and acute neurodegenerative lesions in the septum and corpus callosum. The lesions are associated with an inflammation process. They are less severe and more progressive at low doses. The relevance of high and low doses of icv-STZ to mimic dementia and evaluate new drugs is discussed in the final part of this article.

Highlights

Cerebral aging is associated with the occurrence of neurodegenerative diseases leading to dementia such as Alzheimer’s disease (AD)
STZ alters enzymes involved in the glycolytic cerebral metabolism of glucose [6,7,8] and insulin/IGF pathway leading to an insulin resistance brain state that mimics some of the cerebral alterations occurring in AD [9,10,11,12]
Intracerebroventricular administration of streptozotocin in rodents is used to create an animal model of dementia. The rationale for this model is that STZ induces alterations of insulin/ IGF pathway and glucose metabolism [10,11,12] as well as oxidative stress [15] leading to cerebral alterations and behavioral impairments [15,21]

Summary

Introduction

Cerebral aging is associated with the occurrence of neurodegenerative diseases leading to dementia such as Alzheimer’s disease (AD). These diseases represent critical public health issues and intensive research is required to provide new treatments that counterbalance mechanisms leading to dementia. Animal models are critical to evaluate such therapies and one of these models relies on the intracerebroventricular administration of streptozotocin (icv-STZ). The rationale for this model is two-fold. The icv-STZ model is widely used to evaluate neuroprotective properties of various compounds such as antiinflammatory drugs (cyclooxygenase inhibitors [22], Jun Nterminal kinase inhibitors [23], antioxidants (curcumin [24], Sallyl cysteine [25], selenium [26]), acetylcholinesterase inhibitors (donepezil, tacrine [21,27,28]), antidiabetic drugs (pioglitazone, [29]), cholesterol-lowering drugs (statins [30,31] and others like adrenergic alpha and beta receptors antagonists (carvedilol [32]), protease inhibitors [33] or type-1 phosphodiesterase inhibitors (vinpocetine [13])

Methods

Results

Conclusion