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Heme oxygenase-1 aggravates heat stress-induced neuronal injury and decreases autophagy in cerebellar Purkinje cells of rats.
- Source :
-
Experimental biology and medicine (Maywood, N.J.) [Exp Biol Med (Maywood)] 2013 Jul; Vol. 238 (7), pp. 744-54. Date of Electronic Publication: 2013 Jun 20. - Publication Year :
- 2013
-
Abstract
- We previously reported that heat stroke induces autophagy as a protection mechanism against neurodegeneration in the brain. Heme oxygenase (HO)-1 is a stress protein and can be induced by heat stress (HS). Cerebellar Purkinje cells are selectively vulnerable to heat-induced injury. In this study, we first validated an animal model of HS (38°C for 4 h) in which sustained increase of Purkinje cell injury, HO-1 expression up to 24 h post HS (HS₂₄), and hyperthermia reaching a rectal temperature 41.52 ± 0.32 were observed. In subsequent experiments, we investigated the effects of HO-1 on HS-induced Purkinje cell injury. Rats were divided into four groups: one normothermic control group receiving saline vehicle (1 mL/kg, intraperitoneal [i.p.]) and exposed to 25 for 4 h; and three HS groups receiving saline, or HO-1 inducer haemin (30 mg/kg, i.p.) or HO-1 inhibitor tin protoporphyrin (SnPP, 30 mg/kg, i.p.), respectively, at 12 h prior to HS. HS-induced Purkinje cell injury was further enhanced by HO-1 inducer but attenuated by HO-1 inhibitor as evaluated by immunoreactivity of apoptosis marker (active caspase-3) as well as Fluoro-Jade B histochemistry (staining for degenerating neurons), suggesting a detrimental role of HO-1. Interestingly, the protective autophagy was reduced by HO-1 inducer but enhanced by HO-1 inhibitor as demonstrated by autophagy markers including Beclin-1 and microtubule-associated protein light chain 3 in Purkinje cells. Double immunofluorescent labelling of Beclin-1 or 8-hydroxydeoxyguanosine (an oxidative DNA damage marker) with HO-1 immunoreactivity not only demonstrated their co-localization, but also confirmed that HO-1 negatively regulated Beclin-1 but increased oxidative stress in the same Purkinje cell. Taken together, our results indicate that HO-1 aggravates HS injury in cerebellar Purkinje cells. Our findings shed new light on cell damage mechanisms by HS in central nervous system and may help to provide potential therapeutic foci.
- Subjects :
- 8-Hydroxy-2'-Deoxyguanosine
Animals
Apoptosis
Apoptosis Regulatory Proteins metabolism
Beclin-1
Body Temperature
Caspase 3 metabolism
Cell Count
Dehydration complications
Dehydration pathology
Deoxyguanosine analogs & derivatives
Deoxyguanosine metabolism
Down-Regulation
Hippocampus enzymology
Hippocampus pathology
Hyperthermia, Induced
Male
Microtubule-Associated Proteins metabolism
Nerve Degeneration complications
Nerve Degeneration enzymology
Nerve Degeneration pathology
Oxidative Stress
Rats
Rats, Sprague-Dawley
Time Factors
Autophagy
Heat-Shock Response
Heme Oxygenase-1 metabolism
Purkinje Cells enzymology
Purkinje Cells pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1535-3699
- Volume :
- 238
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Experimental biology and medicine (Maywood, N.J.)
- Publication Type :
- Academic Journal
- Accession number :
- 23788171
- Full Text :
- https://doi.org/10.1177/1535370213493705