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Upregulations of CRH and CRHR1 in the Epileptogenic Tissues of Patients with Intractable Infantile Spasms
Xiao-Lin Yang1, Bing Chen1, Xiao-Qing Zhang1
1Department of Neurosurgery, Second affiliated Hospital, Third Military Medical University, Chongqing, China.
Insights
Corticotropin-releasing hormone (CRH) and its receptor (CRHR1) are upregulated in infantile spasms (IS) brain tissues. Their increased expression correlates with seizure frequency, suggesting CRH pathway involvement in IS pathogenesis.
Area of Science:
- Neuroscience
- Epileptology
- Molecular Biology
Background:
- Infantile spasms (IS) is an age-specific epileptic syndrome with limited treatment options and poor prognosis.
- Excessive endogenous corticotropin-releasing hormone (CRH) is hypothesized to contribute to IS, but human data are scarce.
Purpose of the Study:
- To investigate the expression and distribution of CRH and its receptor type 1 (CRHR1) in surgical tissues from IS patients.
- To explore the correlation between CRH/CRHR1 expression and IS severity.
Main Methods:
- Analysis of surgical tissues from 17 IS patients and 6 autopsy controls.
- Real-time PCR, Western blotting, and immunostaining to quantify mRNA, protein expression, and cellular distribution.
- Spearman rank correlation to analyze relationships between variables.
Main Results:
- CRH and CRHR1 mRNA and protein were significantly upregulated in IS epileptogenic tissues compared to controls.
- CRH localized to neurons; CRHR1 localized to neurons, astrocytes, and microglia.
- CRH and CRHR1 expression levels positively correlated with epileptic spasm frequency.
- Protein kinase C (PKC), a downstream CRHR1 factor, was upregulated and correlated with CRHR1 levels and spasm frequency.
Conclusions:
- The CRH signaling pathway appears to be involved in the epileptogenesis of IS.
- Findings support the hypothesis that CRH plays a role in the pathogenesis of infantile spasms.
Aim:
Infantile spasms (IS) are an age-specific epileptic syndrome with specific clinical symptom and electroencephalogram (EEG) features, lacking treatment options, and a poor prognosis. Excessive endogenous corticotropin-releasing hormone (CRH) in infant brain might result in IS. However, the data from human IS are limited. In our study, we investigated the expressions of CRH and its receptor type 1 (CRHR1) in surgical tissues from patients with IS and autopsy controls.
Methods:
Specimens surgically removed from 17 patients with IS, and six autopsy controls were included in the study. Real-time PCR, Western blotting, and immunostaining were used to detect the expressions of mRNA, protein expression, and distribution. The correlation between variates was analyzed by Spearman rank correlation.
Results:
The expressions of CRH and CRHR1 were significantly upregulated in the epileptogenic tissues of IS patients compared with the control group. CRH was distributed mainly in neurons, while CRHR1 was distributed in neurons, astrocytes, and microglia. The expression levels of CRH and CRHR1 were positively correlated with the frequency of epileptic spasms. Moreover, the expression of protein kinase C (PKC), which was an important downstream factor of CRHR1, was significantly upregulated in the epileptogenic tissues of patients with IS and was positively correlated with the CRHR1 expression levels and the frequency of epileptic spasms.
Conclusion:
These results suggest that the CRH signal transduction pathway might participate in the epileptogenesis of IS, supporting the hypothesis that CRH is related to the pathogenesis of IS.
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