A chronic Alzheimer’s model evoked by mitochondrial poison sodium azide for pharmacological investigations

Szabados, Tamás; Dul, Csaba; Majtényi, Katalin; Hargitai, Judit; Pénzes, Zoltán; Urbanics, Rudolf

doi:10.1016/j.bbr.2004.01.016

Cited by 78 publications

(54 citation statements)

References 34 publications

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“…Rats with excitotoxic lesions in the PCC were not different than control animals in a sucrose consumption test (Bussey et al, 1996). Also, previous studies have shown that rats treated systemically with sodium azide have no change in sensory or motor function, or in exploratory activity in an open field chamber (Bennett and Rose, 1992;Szabados et al, 2004). However, they did have impaired memory for spatial tasks such as the eight-arm radial maze (Bennett and Rose, 1992), Morris water maze , and holeboard task (Callaway et al, 2002).…”

Section: Discussionmentioning

confidence: 93%

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Riha

Rojas

Colorado³

et al. 2008

Neurobiology of Learning and Memory

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The posterior cingulate cortex (PCC) is the brain region displaying the earliest sign of energy hypometabolism in patients with amnestic mild cognitive impairment (MCI) who develop Alzheimer's disease (AD). In particular, the activity of the mitochondrial respiratory enzyme cytochrome oxidase (C.O.) is selectively inhibited within the PCC in AD. The present study is the first experimental analysis designed to model in animals the localized cortical C.O. inhibition found as the earliest metabolic sign of early-stage AD in human neuroimaging studies. Rats were used to model local inhibition of C.O. by direct injection of the C.O. inhibitor sodium azide into the PCC. Learning and memory were examined in a spatial holeboard task and brains were analyzed using quantitative histochemical, morphological and biochemical techniques. Behavioral results showed that sodium azide-treated rats were impaired in their memory of the baited pattern in probe trials as compared to their training scores before treatment, without non-specific behavioral differences. Brain analyses showed that C.O. inhibition was specific to the PCC, and sodium azide increased lipid peroxidation, gliosis and neuron loss, and lead to a network functional disconnection between the PCC and interconnected hippocampal regions. It was concluded that impaired memory by local C.O. inhibition in the PCC may serve to model in animals a metabolic lesion similar to that found in patients with amnestic MCI and early-stage AD. This model may be useful as an in vivo testing platform to investigate neuroprotective strategies to prevent or reduce the amnestic effects produced by posterior cingulate energy hypometabolism.

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Section: Discussionmentioning

confidence: 93%

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Riha

Rojas

Colorado³

et al. 2008

Neurobiology of Learning and Memory

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“…Azide has been used in the development of models of chronic Alzheimer's disease and amyotrophic lateral sclerosis (ALS) (Kaal et al, 2000;Szabados et al, 2004). Sodium azide administered to rats at 45 mg/kg/day caused both cognitive deficits and histopathological changes similar to changes caused by Alzheimer's disease (Szabados et al, 2004), while the administration of up to 100 μM azide caused dose dependent death in motoneurons (Kaal et al, 2000). A concentration of 30 μM was lethal to motoneurons as compared to the survival of 44% of interneurons at the same concentration (Kaal et al, 2000).…”

Section: 14mentioning

confidence: 99%

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Foster

Galeffi

Gerich

et al. 2006

Progress in Neurobiology

166

135

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Mitochondria are critical for cellular ATP production; however, recent studies suggest that these organelles fulfill a much broader range of tasks. For example, they are involved in the regulation of cytosolic Ca 2+ levels, intracellular pH and apoptosis, and are the major source of reactive oxygen species (ROS). Various reactive molecules that originate from mitochondria, such as ROS, are critical in pathological events, such as ischemia, as well as in physiological events such as long-term potentiation, neuronal-vascular coupling and neuronal-glial interactions. Due to their key roles in the regulation of several cellular functions, the dysfunction of mitochondria may be critical in various brain disorders. There has been increasing interest in the development of tools that modulate mitochondrial function, and the refinement of techniques that allow for real time monitoring of mitochondria, particularly within their intact cellular environment. Innovative imaging techniques are especially powerful since they allow for mitochondrial visualization at high resolution, tracking of mitochondrial structures and optical real time monitoring of parameters of mitochondrial function. Among the techniques discussed are the uses of classic imaging techniques such as rhodamine-123, the highly advanced semi-conductor nanoparticles (quantum dots), and wide field microscopy as well as high-resolution multi-photon imaging. We have highlighted the use of these techniques to study mitochondrial function in brain tissue and have included studies from our laboratories in which these techniques have been successfully applied.

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“…Similarly, sodium azide (NaN 3 ) is a substance that is acutely neurotoxic [11] . Several studies conducted on its biological interaction with the central nervous system established it as a consistent and potent neurotoxin [12][13][14] . Selectively reduced complex IV activity is a pathogenic feature of postmortem AD brains and the inhibition of this complex could be evoked by the chronic administration of NaN 3 in animals [14] .…”

Section: Introductionmentioning

confidence: 99%

“…Several studies conducted on its biological interaction with the central nervous system established it as a consistent and potent neurotoxin [12][13][14] . Selectively reduced complex IV activity is a pathogenic feature of postmortem AD brains and the inhibition of this complex could be evoked by the chronic administration of NaN 3 in animals [14] . Partial inhibition of the mitochondrial respiratory chain produces free radicals, diminishes aerobic energy metabolism and causes excitotoxic damage that creates a deleterious spiral leading to neurodegeneration [15] .…”

Section: Introductionmentioning

confidence: 99%

Cerebellar Molecular and Cellular Characterization in Rat Models of Alzheimer's Disease: Neuroprotective Mechanisms of <b><i>Garcinia</i></b> Biflavonoid Complex

et al. 2017

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Background: Recent evidences suggest that cerebellar degeneration may be associated with the development of Alzheimer's disease (AD). However, previous reports were mainly observational, lacking substantial characterization of cellular and molecular cerebellar features during AD progression. Purpose: This study is aimed at characterizing the cerebellum in rat models of AD and assessing the corresponding neuroprotective mechanisms of Garcinia biflavonoid complex (GBc). Methods: Male Wistar rats were grouped and treated alone or in combination with PBS (ad libitum)/day, corn oil (CO; 2 mL/kgBw/day), GBc (200 mg/kgBw/day), sodium azide (NaN₃) (15 mg/kgBw/day) and aluminium chloride (AlCl₃) (100 mg/kgBw/day). Groups A and B received PBS and CO, respectively; C received GBc; D received NaN₃; E received AlCl₃; F received NaN₃ then GBc subsequently; G received AlCl₃ then GBc subsequently; H received NaN₃ and GBc simultaneously while I received AlCl₃ and GBc simultaneously. Following treatments, cerebellar cortices were processed for histology, immunohistochemistry and colorimetric assays. Results: Our data revealed that cryptic granule neurons and pyknotic Purkinje cell bodies (characterized by short dendritic/axonal processes) correspond to indistinctly demarcated cerebellar layers in rats treated with AlCl₃ and NaN₃. These correlates, with observed hypertrophic astrogliosis, increased the neurofilament deposition, depleted the antioxidant system-shown by expressed superoxide dismutase and glutathione peroxidase, and cerebellar glucose bioenergetics dysfunction-exhibited in assayed lactate dehydrogenase and glucose-6-phosphate dehydrogenase. We further showed that GBc reverses cerebellar degeneration through modulation of neurochemical signaling pathways and stressor molecules that underlie AD pathogenesis. Conclusion: Cellular, molecular and metabolic neurodegeneration within the cerebellum is associated with AlCl₃ and NaN₃-induced AD while GBc significantly inhibits corresponding neurotoxicity and is more efficacious when pre-administered.

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A chronic Alzheimer’s model evoked by mitochondrial poison sodium azide for pharmacological investigations

Cited by 78 publications

References 34 publications

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Animal model of posterior cingulate cortex hypometabolism implicated in amnestic MCI and AD

Optical and pharmacological tools to investigate the role of mitochondria during oxidative stress and neurodegeneration

Cerebellar Molecular and Cellular Characterization in Rat Models of Alzheimer's Disease: Neuroprotective Mechanisms of <b><i>Garcinia</i></b> Biflavonoid Complex

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