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Epigenetic modulation of the MAPK pathway prevents isoflurane-induced neuronal apoptosis and cognitive decline in
Lei Huang1, Hai-Bin Fang1, Hui-Hui Cheng1
1Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
Abstract:
Isoflurane is a broadly used inhalation anesthetic that causes cognitive impairment in rodent models as well as humans. Although previous studies suggested an association between isoflurane exposure and neuro-inflammation, apoptosis and mitochondrial dysfunction, the pathogenesis of isoflurane-induced cognitive decline remains elusive. In the present study, 22-month-old male Sprague-Dawley male rats (n=96) were divided into three groups: Control (Cont), isoflurane (ISO) and MS-275 pre-treated groups. The rats were sacrificed following exposure to isoflurane and a cognitive test. The hippocampus of each animal was harvested for quantitative PCR, TUNEL staining and western blot analysis. Histone deacetylases (HDAC)-1, -2 and -3 exhibited a significant increase at the gene and protein expression levels, whereas negligible mRNA expressions were observed for genes HDAC 4-11 (P>0.05; compared with Cont). Pre-treatment with the HDAC inhibitor MS-275 significantly inhibited the increase in TUNEL-positive cells induced by isoflurane exposure (70.72% decrease; P<0.001; compared with ISO). Furthermore, MS-275 significantly decreased caspase-3 and Bax expression levels while increasing Bcl-2 protein expression. The isoflurane-induced changes in the MAPK pathway signaling proteins ERK1/2, JNK and p38 were also reversed with MS-275 pre-treatment. Finally, in a Morris water maze test, the time to find a hidden platform was reduced in MS-275 pre-treated rats, compared with the ISO group. Therefore, the present study provided insight into the effect of isoflurane exposure on neuronal apoptosis pathways, as well as cognitive decline via epigenetic programming of MAPK signaling in aged rats.
Insights
Isoflurane anesthesia impairs cognition in aged rats by increasing histone deacetylases (HDACs) and neuronal apoptosis. Pre-treating with an HDAC inhibitor, MS-275, reversed these effects and improved cognitive function.
Area of Science:
- Neuroscience
- Anesthesiology
- Epigenetics
Background:
- Isoflurane anesthesia is widely used but linked to cognitive impairment.
- The exact mechanisms behind isoflurane-induced cognitive decline, including neuro-inflammation and apoptosis, are not fully understood.
- Histone deacetylases (HDACs) play a role in epigenetic regulation and have been implicated in neurological disorders.
Purpose of the Study:
- To investigate the role of HDACs in isoflurane-induced cognitive decline in aged rats.
- To examine the protective effects of the HDAC inhibitor MS-275 against isoflurane-induced neuronal damage and cognitive impairment.
- To elucidate the impact of isoflurane and MS-275 on apoptosis and MAPK signaling pathways.
Main Methods:
- Aged male Sprague-Dawley rats were divided into control, isoflurane (ISO), and MS-275 pre-treated groups.
- Hippocampal tissues were analyzed using quantitative PCR, TUNEL staining, and Western blot.
- Cognitive function was assessed using the Morris water maze test.
Main Results:
- Isoflurane exposure significantly increased the expression of HDAC-1, -2, and -3.
- MS-275 pre-treatment markedly reduced isoflurane-induced neuronal apoptosis (TUNEL-positive cells, caspase-3, Bax) and increased Bcl-2 expression.
- MS-275 reversed isoflurane-induced alterations in MAPK pathway signaling (ERK1/2, JNK, p38) and improved performance in the Morris water maze.
Conclusions:
- Isoflurane exposure promotes cognitive decline in aged rats through epigenetic modulation of neuronal apoptosis and MAPK signaling via HDAC upregulation.
- Pre-treatment with the HDAC inhibitor MS-275 offers neuroprotection against isoflurane-induced cognitive impairment.
- Targeting HDACs may represent a therapeutic strategy to mitigate the adverse cognitive effects of isoflurane anesthesia.
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