1. Heme oxygenase-1 aggravates heat stress-induced neuronal injury and decreases autophagy in cerebellar Purkinje cells of rats.
- Author
-
Li CW, Lin YF, Liu TT, and Wang JY
- 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
- 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 (HSâ‚‚â‚„), 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.
- Published
- 2013
- Full Text
- View/download PDF