The homeostasis of iron and suppression of HO-1 involved in the protective effects of nimodipine on neurodegeneration induced by aluminum overloading in mice
ABSTRACT Aluminum intoxication can cause damage to the cognitive function and neurodegenerative diseases. In the present study, we investigated the role of iron homeostasis and heme oxygenase-1 (HO-1) expression in the protective effects of nimodipine on the neurodegeneration induced by aluminum overloading in mice. 2 microl of 0.25% aluminum chloride solution was intracerebroventricularly injected once a day for five days to induce the neurodegeneration of mice. Nimodipine was administered by intragastric gavage (80 mg/kg per day) for 30 days. We observed that nimodipine could improve the performance of behavior test related to the learning and memory function and ameliorate pathological changes of hippocampi caused by aluminum. Results of western blot, immunohistochemistry study, biochemical test and inductively coupled plasma-atomic emission spectrometry showed that nimodipine could suppress the increased expression of HO-1 protein, and decrease the elevation of both HO activity and iron level in hippocampi, induced by aluminum overloading. These results indicate that nimodipine can suppress the neurodegenerative development induced by aluminum overloading and the mechanism of its action is at least partly related to keeping the homeostasis of iron through blunting the expression of HO-1 in hippocampus.
- SourceAvailable from: Kostas Pantopoulos
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- "Thus, HO-1 has been shown to be neuroprotective in animal models of spinal cord injury (Lin et al. 2007), excitotoxicity (Ahmad et al. 2006), traumatic brain injury (Beschorner et al. 2000), and ischemia (Panahian et al. 1999). On the other hand, enhanced HO activity proved detrimental in experimental intracerebral hemorrhage (Wang and Dore 2007) and aluminum neurotoxicity (Yuan et al. 2008) and exacerbated nigrostriatal damage in the MPTP mouse model of PD (Fernandez-Gonzalez et al. 2000). In this study, chronic over-expression of HO-1 in astrocytes of GFAP. "
ABSTRACT: The mechanisms responsible for pathological iron deposition in the aging and degenerating mammalian CNS remain poorly understood. The stress protein, HO-1 mediates the degradation of cellular heme to biliverdin/bilirubin, free iron, and CO and is up-regulated in the brains of persons with Alzheimer's disease and Parkinson's disease. HO-1 induction in primary astroglial cultures promotes deposition of non-transferrin iron, mitochondrial damage and macroautophagy, and predisposes cocultured neuronal elements to oxidative injury. To gain a better appreciation of the role of glial HO-1 in vivo, we probed for aberrant brain iron deposition using Perls' method and dynamic secondary ion mass spectrometry in novel, conditional GFAP.HMOX1 transgenic mice that selectively over-express human HO-1 in the astrocytic compartment. At 48 weeks, the GFAP.HMOX1 mice exhibited increased deposits of glial iron in hippocampus and other subcortical regions without overt changes in iron-regulatory and iron-binding proteins relative to age-matched wild-type animals. Dynamic secondary ion mass spectrometry revealed abundant FeO(-) signals in the transgenic, but not wild-type, mouse brain that colocalized to degenerate mitochondria and osmiophilic cytoplasmic inclusions (macroautophagy) documented by TEM. Sustained up-regulation of HO-1 in astrocytes promotes pathological brain iron deposition and oxidative mitochondrial damage characteristic of Alzheimer's disease-affected neural tissues. Curtailment of glial HO-1 hyperactivity may limit iron-mediated cytotoxicity in aging and degenerating neural tissues.Journal of Neurochemistry 08/2012; 123(2):325-36. DOI:10.1111/j.1471-4159.2012.07914.x · 4.24 Impact Factor
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- "Moreover, overexpression of HO-1 in dopaminergic cells (MN9D) was found to increase both intracellular Fe and ROS following exposure to polychlorinated biphenyls (PCB), while inhibition of HO-1 prevented PCB-induced ROS and cell death (Lee et al., 2006). In addition, suppressing the expression of HO-1 with nimperidine decreased hippocampal Fe and ROS following exposure to aluminum (Yuan et al., 2008). In our study, inhibition of HO-1 activity curbed the release of Mn-potentiated inflammatory cytokines by LPS-activated microglia (Fig 5). "
ABSTRACT: Excessive manganese (Mn) exposure increases output of glial-derived inflammatory products, which may indirectly contribute to the neurotoxic effects of this essential metal. In microglia, Mn increases hydrogen peroxide (H(2)O(2)) release and potentiates lipopolysaccharide (LPS)-induced cytokines (TNF-α, IL-6) and nitric oxide (NO). Inducible heme-oxygenase (HO-1) plays a role in the regulation of inflammation and its expression is upregulated in response to oxidative stressors, including metals and LPS. Because Mn can oxidatively affect neurons both directly and indirectly, we investigated the effect of Mn exposure on the induction of HO-1 in resting and LPS-activated microglia (N9) and dopaminergic neurons (N27). In microglia, 24h exposure to Mn (up to 250 μM) had minimal effects on its own, but it markedly potentiated LPS (100 ng/ml)-induced HO-1 protein and mRNA. Inhibition of microglial HO-1 activity with two different inhibitors indicated that HO-1 is a positive regulator of the Mn-potentiated cytokine output and a negative regulator of the Mn-induced H(2)O(2) output. Mn enhancement of LPS-induced HO-1 does not appear to be dependent on H(2)O(2) or NO, as Mn+LPS-induced H(2)O(2) release was not greater than the increase induced by Mn alone and inhibition of iNOS did not change Mn potentiation of HO-1. However, because Mn exposure potentiated the LPS-induced nuclear expression of small Maf proteins, this may be one mechanism Mn uses to affect the expression of HO-1 in activated microglia. Finally, the potentiating effects of Mn on HO-1 appear to be glia-specific for Mn, LPS, or Mn+LPS did not induce HO-1 in N27 neuronal cells.NeuroToxicology 09/2011; 32(6):683-92. DOI:10.1016/j.neuro.2011.09.002 · 3.05 Impact Factor
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ABSTRACT: The heme oxygenases (HOs), responsible for the degradation of heme to biliverdin/bilirubin, free iron and CO, have been heavily implicated in mammalian CNS aging and disease. In normal brain, the expression of HO-2 is constitutive, abundant and fairly ubiquitous, whereas HO-1 mRNA and protein are confined to small populations of scattered neurons and neuroglia. In contradistinction to HO-2, the ho-1 gene (Hmox1) is exquisitely sensitive to induction by a wide range of pro-oxidant and other stressors. In Alzheimer disease and mild cognitive impairment, immunoreactive HO-1 protein is over-expressed in neurons and astrocytes of the cerebral cortex and hippocampus relative to age-matched, cognitively intact controls and co-localizes to senile plaques, neurofibrillary tangles, and corpora amylacea. In Parkinson disease, HO-1 is markedly over-expressed in astrocytes of the substantia nigra and decorates Lewy bodies in affected dopaminergic neurons. HMOX1 is also up-regulated in glial cells surrounding human cerebral infarcts, hemorrhages and contusions, within multiple sclerosis plaques, and in other degenerative and inflammatory human CNS disorders. Heme-derived free ferrous iron, CO, and biliverdin/bilirubin are biologically active substances that have been shown to either ameliorate or exacerbate neural injury contingent upon specific disease models employed, the intensity and duration of HO-1 expression and the nature of the prevailing redox microenvironment. In 'stressed' astroglia, HO-1 hyperactivity promotes mitochondrial sequestration of non-transferrin iron and macroautophagy and may thereby contribute to the pathological iron deposition and bioenergetic failure amply documented in Alzheimer disease, Parkinson disease and other aging-related neurodegenerative disorders. Glial HO-1 expression may also impact cell survival and neuroplasticity in these conditions by modulating brain sterol metabolism and proteosomal degradation of neurotoxic protein aggregates.Journal of Neurochemistry 06/2009; 110(2):469-85. DOI:10.1111/j.1471-4159.2009.06160.x · 4.24 Impact Factor