Ladostigil prevents gliosis, oxidative–nitrative stress and memory deficits induced by intracerebroventricular injection of streptozotocin in rats
Introduction
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and widespread loss of neurons and their synapses in the cerebral cortex and hippocampus (Katzman, 1986). In AD and other age-related neurodegenerative conditions recruitment and activation of microglia and astrocytes occur before pathological and clinical signs of the disease (Mrak and Griffin, 2005, Strohmeyer and Rogers, 2001). Activated microglia and astrocytes can release cytokines, reactive oxygen species (ROS) and nitric oxide (NO) that may contribute to the memory deficits (Tuppo and Arias, 2005). Glial changes also play a role in the cognitive decline that occurs during normal human aging even in the absence of overt neuron loss (Morgan et al., 1999, Nichols et al., 1993).
In a detailed histological examination of the brain after intracerebroventricular (icv) injection of streptozotocin (STZ) in rats we found that microglial activation occurs in discrete areas (Shoham et al., 2003). icv STZ was originally given to mimic the decrement in cerebral glucose metabolism (Duelli et al., 1994) seen in the early stages of AD (Arnaiz et al., 2001). While parenteral injection of STZ induces diabetes, by damaging pancreatic beta cells possibly through the generation of ROS (Takasu et al., 1991), STZ has no effect on blood sugar when given icv (Mayer et al., 1990), but decreases glucose utilization in discrete areas of the cortex and hippocampus (Duelli et al., 1994). It also damages the septohippocampal system (Prickaerts et al., 1999), and increases brain levels of malondialdehyde, an indirect measure of oxidative stress (Sharma and Gupta, 2001). Memory deficits are seen 3–8 weeks later, particularly after three icv injections of STZ (Lannert and Hoyer, 1998) and can be reduced by chronic treatment with antioxidants, melatonin and resveratrol (Sharma and Gupta, 2001, Sharma and Gupta, 2002), supporting a role of ROS in their aetiology.
Ladostigil (TV3326, N-propargyl-(3R)-aminoindan-5-yl-ethyl methyl carbamate, hemitartrate) is currently being developed as a treatment for AD (Weinstock et al., 2003). It was designed to combine the cholinesterase (ChE) inhibitory activity of rivastigmine with the neuroprotective actions of rasagiline, a monoamine oxidase (MAO-B) inhibitor which slows the progression of Parkinson's disease (Olanow, 2006). Rasagiline protects against the sequelae of head injury in rats (Huang et al., 1999) and prevents cytotoxicity in cultured neuronal cells induced by ROS and NO and by serum deprivation (Youdim and Weinstock, 2001). Since the neuroprotective effect is shared by similar concentrations of its S-enantiomer (TV1022) and by ladostigil that are 100–1000-fold less potent as MAO-B inhibitors, it is unlikely to result from MAO inhibition.
The aims of the present study were twofold: (a) to detect and quantify glial changes and oxidative–nitrative stress in discrete regions in the cortex and hippocampus 1 week after a single icv injection of STZ, before neuronal damage and memory deficits occur; (b) to determine whether chronic treatment with ladostigil can prevent the glial changes and subsequent memory deficits induced by icv STZ.
Some of these data were presented at a meeting of the Israel Society for Neuroscience, December 2005 (Weinstock et al., 2005).
Section snippets
Animals
The study was performed on male Sprague–Dawley rats (Harlan, Jerusalem) weighing 320–340 g, aged four months, according to the guidelines of the University Committee for Institutional Animal Care and based on those of the National Institutes of Health, USA. The rats were housed for 1 week prior to surgery in the Animal House at an ambient temperature of 21 ± 1 °C and a 12 h diurnal light cycle (lights on at 07:00 h).
Experimental protocol
Ninety-four rats were anesthetised by an intraperitoneal injection of Equithesin 0.3
Glial changes induced by icv STZ in vicinity of cannula penetration site
In the motor and cingulate cortex around the cannula penetration site three zones of gliosis could be distinguished seven days after icv STZ. Zone (i) contained microglia that resembled macrophages, with round shaped soma devoid of processes, but was almost free of astrocytes; zone (ii) had activated microglia with polymorphic shaped soma and a variety of fibrous processes and activated astrocytes with elongated processes but no soma; zone (iii) had resident microglia resembling those in the
Discussion
The major new finding in this study is that icv injection in rats of STZ induced reactive gliosis and oxidative–nitrative stress before the induction of memory deficits. The reactive gliosis involved microglia and astrocytes in the cingulate and motor cortex around the area of cannula penetration, CA1 region of the hippocampus, and in the corpus callosum, medial and lateral septum close to the lateral ventricle. Oxidative–nitrative stress was present in the form of NT immunoreactivity in
Acknowledgement
The authors wish to thank Teva Pharmaceuticals Ltd for financial support and for performing the measurements of monoamine oxidase activity. The funding source had no direct or indirect role in collecting analyzing or interpreting the data, writing the paper or deciding to submit it for publication.
References (36)
- et al.
Aniracetam restores object recognition impaired by age, scopolamine, and nucleus basalis lesions
Pharmacol. Biochem. Behav.
(1996) - et al.
Regulation of glucose metabolism by nitrosative stress in neural cells
Mol. Asp. Med.
(2004) - et al.
Aminopyridazines inhibit beta-amyloid-induced glial activation and neuronal damage in vivo
Neurobiol. Aging
(2004) - et al.
Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats
Int. J. Dev. Neurosci.
(1994) - et al.
A new and rapid colorimetric determination of acetylcholinesterase activity
Biochem. Pharmacol.
(1961) Neurons, glia, and plasticity in normal brain aging
Neurobiol. Aging
(2003)- et al.
Neuroprotective effect of rasagiline, a selective monoamine oxidase-B inhibitor, against closed head injury in the mouse
Eur. J. Pharmacol.
(1999) - et al.
Anti-apoptotic action of anti-Alzheimer drug, TV3326 [(N-propargyl)-(3R)-aminoindan-5-yl]-ethyl methyl carbamate, a novel cholinesterase-monoamine oxidase inhibitor
Neurosci. Lett.
(2003) - et al.
Effects of changes in peripheral and cerebral glucose metabolism on locomotor activity, learning and memory in adult male rats
Brain Res.
(1990) Down-regulation of microglial activation may represent a practical strategy for combating neurodegenerative disorders
Med. Hypotheses
(2006)
Inflammatory processes in Alzheimer's disease
Prog. Neuropsychopharmacol. Biol. Psychiatry
Neuroprotection by memantine against neurodegeneration induced by beta-amyloid(1–40)
Brain Res.
The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction
Neuroscience
Glia and their cytokines in progression of neurodegeneration
Neurobiol. Aging
GFAP mRNA increases with age in rat and human brain
Neurobiol. Aging
Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis
Behav. Brain Res.
Effect of chronic treatment of melatonin on learning, memory and oxidative deficiencies induced by intracerebroventricular streptozotocin in rats
Pharmacol. Biochem. Behav.
Chronic treatment with trans resveratrol prevents intracerebroventricular streptozotocin induced cognitive impairment and oxidative stress in rats
Life Sci.
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