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

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.

Staging of cognitive deficits and neuropathological and ultrastructural changes in streptozotocin-induced rat model of Alzheimer’s disease

“…Icv administration of low STZ doses does not induce a systemic diabetic condition in rats, but has been convincingly shown to induce insulin-resistant brain state characterized by altered tyrosine kinase activity of IR and dysfunctional signalling downstream the IR signaling pathways (Agrawal et al 2010(Agrawal et al , 2011Grünblatt et al 2007;Lester-Coll et al 2006;Osmanovic-Barilar et al 2014;Salkovic-Petrisic et al 2006;Steen et al 2005), accompanied by a decrease in brain glucose and energy metabolism (Hoyer and Lannert 2007;Lannert and Hoyer 1998;Nitsch and Hoyer 1991;Plaschke and Hoyer 1993). Additionally, the STZ-icv rat model has been demonstrated to develop remarkable behavioral and neuropathological AD-like features, in particular cognitive (Mayer et al 1990) and brain cholinergic deficits (Hellweg et al 1992), as well as oxidative stress (Correia et al 2013;Sharma and Gupta 2001), neuroinflammation, and astrogliosis (Chen et al 2013;Javed et al 2011;Kraska et al 2012;Prickaerts et al 1999Prickaerts et al , 2000Rodrigues et al 2010;Shoham et al 2003Shoham et al , 2007. Severely affected STZ-icv rats also demonstrate extensive cell loss, inferred from increase in the volume of the ventricular system (Kraska et al 2012;Prickaerts et al 2000;Shoham et al 2003), and a significant enlargement of the trans-Golgi compartment in cortical neurons at the ultrastructural level (Grieb et al 2004).…”

“…Additionally, the STZ-icv rat model has been demonstrated to develop remarkable behavioral and neuropathological AD-like features, in particular cognitive (Mayer et al 1990) and brain cholinergic deficits (Hellweg et al 1992), as well as oxidative stress (Correia et al 2013;Sharma and Gupta 2001), neuroinflammation, and astrogliosis (Chen et al 2013;Javed et al 2011;Kraska et al 2012;Prickaerts et al 1999Prickaerts et al , 2000Rodrigues et al 2010;Shoham et al 2003Shoham et al , 2007. Severely affected STZ-icv rats also demonstrate extensive cell loss, inferred from increase in the volume of the ventricular system (Kraska et al 2012;Prickaerts et al 2000;Shoham et al 2003), and a significant enlargement of the trans-Golgi compartment in cortical neurons at the ultrastructural level (Grieb et al 2004). In addition, increased Aβ 1-42 and hyperphosphorylated tau immunoreactivity have been detected in the hippocampus of STZ-icv rats and mice (Chen et al 2013;Correia et al 2013;Deng et al 2009;Kosaraju et al 2013;Shingo et al 2012).…”

Neuroprotective effect of renin angiotensin system blockers on experimentally induced Alzheimer's disease in rats

“…8 The rationale for this model is that STZ, by the dose employed in this study, is shown to induce oxidative stress and inflammation leading to neuronal loss. 10 STZ also alters enzymes involved in the glycolytic cerebral metabolism of glucose depleting ATP synthesis. Low ATP availability in the brain is followed by faulty Aβ-P metabolism and hyper-phosphorylation of the tau-protein that induce production of neuritic plaques and NFT, the prominent histopathological markers of AD.…”

“…10 The site of injection was 2 mm from either side of the midline on a line drawn through the anterior base of the ears. From the second day after ICV-STZ injection, rats were randomly assigned, and grouping of animals continued as follows:…”

The diabetic brain and cognition

“…Insulin resistance, hyperinsulinemia, and hyperglycemia can promote the onset of AD (Rönnemaa et al 2008;de Oliveira Lanna et al 2014) by accelerating tau phosphorylation and neuritic plaque formation (Bitel et al 2012;Matsuzaki et al 2010) and, overlapping with AD pathology, aggravate the progression of neurodegeneration due to OS, mitochondrial dysfunction, neuroinflammation, etc. as a common background (Carvalho et al 2015;Kraska et al 2012;RorizFilho et al 2009;Rosales-Corral et al 2015). Thus, impaired insulin signaling may be a possible link between AD and DM (Jellinger 2015a, b;Sato et al 2011).…”