The homeostasis of iron and suppression of HO-1 involved in the protective effects of nimodipine on neurodegeneration induced by aluminum overloading in mice
Department of Pharmacology of Chong Qing Medical University, China. European Journal of Pharmacology
(Impact Factor: 2.53).
06/2008; 586(1-3):100-5. DOI: 10.1016/j.ejphar.2008.02.033
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.
Available from: Hyman Schipper
- "The heme oxygenase reaction may either confer cytoprotection by converting prooxidant heme and hemoproteins to the antioxidants biliverdin and bilirubin (Schipper et al., 2009a) or, conversely , liberate CO and ferrous iron, which may exacerbate oxidative stress within the mitochondrial and other cellular compartments (Zhang and Piantadosi, 1992; Schipper et al., 2009a). HO activity has been shown to afford neuroprotection (Panahian et al., 1999; Beschorner et al., 2000; Ahmad et al., 2006; Lin et al., 2007) or enhance vulnerability in various experimental models of neural injury and disease (Fernandez-Gonzalez et al., 2000; Wang and Doré, 2007; Yuan et al., 2008). HO-1 protein is overexpressed in astrocytes and decorates neuronal Lewy bodies in the substantia nigra of patients with PD (Schipper et al., 1998). "
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ABSTRACT: Delineation of key molecules that act epigenetically to transduce diverse stressors into established patterns of disease would facilitate the advent of preventive and disease-modifying therapeutics for a host of neurological disorders. Herein, we demonstrate that selective overexpression of the stress protein heme oxygenase-1 (HO-1) in astrocytes of novel GFAP.HMOX1 transgenic mice results in subcortical oxidative stress and mitochondrial damage/autophagy; diminished neuronal reelin content (males); induction of Nurr1 and Pitx3 with attendant suppression of their targeting miRNAs, 145 and 133b; increased tyrosine hydroxylase and α-synuclein expression with downregulation of the targeting miR-7b of the latter; augmented dopamine and serotonin levels in basal ganglia; reduced D1 receptor binding in nucleus accumbens; axodendritic pathology and altered hippocampal cytoarchitectonics; impaired neurovascular coupling; attenuated prepulse inhibition (males); and hyperkinetic behavior. The GFAP.HMOX1 neurophenotype bears resemblances to human schizophrenia and other neurodevelopmental conditions and implicates glial HO-1 as a prime transducer of inimical (endogenous and environmental) influences on the development of monoaminergic circuitry. Containment of the glial HO-1 response to noxious stimuli at strategic points of the life cycle may afford novel opportunities for the effective management of human neurodevelopmental and neurodegenerative conditions.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2012; 32(32):10841-53. DOI:10.1523/JNEUROSCI.6469-11.2012 · 6.34 Impact Factor
Available from: Kostas Pantopoulos
- "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. "
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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 · 4.28 Impact Factor
Available from: Nikolay M Filipov
- "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). "
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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 · 3.38 Impact Factor
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