Expression of corticotropin releasing hormone and its receptors in infantile spasm_Journal of Epilepsy

Authors：

YANGXiaolin ¹ , ZHANGXiaoqing ¹ , CHENBing ¹ , LIWei ¹ , YANGMeihua ¹ , CHENXin ¹ , ZHANGWei ¹ , YANGHui ¹ , ZOULiping ² ,  LIUShiyong ¹

1. Department of Neurosurgery, Xinqiao Hospital, the Third Military Medical Uuniversity, Chongqing 400037, China;
2. Department of Pediatrics, Peoples Liberation Army General Hospital, Beijing 100853, China;

Corresponding author：

LIUShiyong, Email: Liushi2425@163.com

Keywords：

Infantile spasm; Corticotropin releasing hormone; Corticotropin releasing hormone receptor 1; Protein kinase C

DOI：

10.7507/2096-0247.20170001

Video：

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ObjectiveThe purpose of this study was to explore the expression of Corticotropin releasing hormone (CRH), Corticotropin releasing hormone receptor 1 (CRHR1), Protein kinase C (PKC) in epileptogenic zone of Infantile spasm (IS).MethodsCollected 17 cases of tissues of IS patients from operation and 6 cases of normal brain tissues from clinical autopsy during June 2011 to June 2014. Westen blot was used to detected the protein expression of CRH, CRHR1, PKC. PCR was used to exam the mRNA expression of CRH, CRHR1, PKC. Immunohistochemistry and fluorescenceimmuno assay were used to detect the expression of CRH, CRHR1, PKC.ResultsThe mRNA expression of CRH and CRHR1 in IS group are higher than control group, and the protein expression of CRH and CRHR1 in IS group are higher than control group. CRH are slightly expressed in the controls, medium and strong expressed in IS, CRH and NF200 both expressed in IS; CRH is negative in GFAP positive astrocyte; CRH is negative in HLA positive microglial cell. CRHR1 are slightly and medium expressed in the controls, medium and strong expressed in IS, CRHR1 and NF200 both expressed in IS; CRHR1 and GFAP are both positive in astrocyte; CRHR1 and HLA are both positive in microglial cell. PKC are slightly and medium expressed in the controls, medium and strong expressed in IS, PKC and NF200 both expressed in IS; PKC and GFAP are both positive in astrocyte; PKC and HLA are both positive in microglial cell. Spearman analysis showed positive correlation between the expression of CRH, CRHR1, PKC with epileptic spasm in IS patients, as well as positive correlation between PKC with CRHR1.ConclusionsOver expression of CRH, CRHR1, PKC with epileptic spasm in IS patients were positive related with epileptic seizure in IS patients, indicated that CRH signal pathway is related with IS pathogenesis.

Citation： YANGXiaolin, ZHANGXiaoqing, CHENBing, LIWei, YANGMeihua, CHENXin, ZHANGWei, YANGHui, ZOULiping, LIUShiyong. Expression of corticotropin releasing hormone and its receptors in infantile spasm. Journal of Epilepsy, 2017, 3(1): 3-14. doi: 10.7507/2096-0247.20170001 Copy

1.	Sorel L, Dusaucy-Bauloye A. Findings in 21 cases of Gibbs' hypsarrhythmia; spectacular effectiveness of ACTH. Acta Neurol Psychiatr Belg, 1958, 58(7):130-141.
2.	Baram TZ, Mitchell WG, Hanson RA, et al. Cerebrospinal fluid corticotropin and cortisol are reduced in infantile spasms. Pediatr Neurol, 1995, 13(4):108-110.
3.	Brunson KL, Khan N, Eghbal-Ahmadi M, et al. Corticotropin (ACTH) acts directly on amygdala neurons to down-regulate corticotropin-releasing hormone gene expression. Ann Neurol, 2001, 49(5):304-312.
4.	Brunson KL, Eghbal-Ahmadi M, Baram TZ. How do the many etiologies of West syndrome lead to excitability and seizures? The corticotropin releasing hormone excess hypothesis. Brain & Development, 2001, 23(10):533-538.
5.	Lovenberg TW, Liaw CW, Grigoriadis DE, et al. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proceedings of the National Academy of Sciences of the United States of America, 1995, 92(7):836-840.
6.	Grammatopoulos DK, Chrousos GP. Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends in Endocrinology and Metabolism, 2002, 13(6):436-444.
7.	Grabaliskas G, Chapman H, Wheal HV. Role of protein kinase c in modulation of excitability of CA1 pyramidal neurons in the rat. Neuroscience, 2006, 139(4):1301-1313.
8.	Asano E, Chugani DC, Juhasz C, et al. Surgical treatment of west syndrome. Brain Dev, 2001, 23(10):668-676.
9.	Hollrigel GS, Chen K, Baram TZ, et al. The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats. Neuroscience, 1998, 84(2):71-79.
10.	Baram TZ, Hatalski CG. Neuropeptide-mediated excitability:a key triggering mechanism for seizure generation in the developing brain. Trends in neurosciences, 1998, 21(3):471-476.
11.	Aldenhoff JB, Gruol DL, Rivier J, et al. Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons. Science (New York, N.Y.), 1983, 221(7):875-857.
12.	Wang W, Dow KE, Fraser DD. Elevated corticotropin releasing hormone/corticotropin releasing hormone-R1 expression in postmortem brain obtained from children with generalized epilepsy. Annals of Neurology, 2001, 50(2):404-409.
13.	Galanopoulou AS. Basic mechanisms of catastrophic epilepsy-overview from animal models. Brain & Development, 2013, 35(8):748-756.
14.	Baram TZ, Chalmers DT, Chen C, et al. The CRF1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain:in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist. Brain Research, 1997, 770(8):89-95.
15.	Wang XD, Rammes G, Kraev I, et al. Forebrain CRF (1) modulates early-life stress-programmed cognitive deficits. J Neurosci, 2011, 31(11):13625-13634.
16.	Brunson KL, Grigoriadis DE, Lorang MT, et al. Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain. Exp Neurol, 2002, 176(4):75-86.
17.	Blank T, Nijholt I, Grammatopoulos DK, et al. Corticotropin-releasing factor receptors couple to multiple G-proteins to activate diverse intracellular signaling pathways in mouse hippocampus:role in neuronal excitability and associative learning. J Neurosci, 2003, 23(6):700-707.
18.	Silva AP, Lourenco J, Xapelli S, et al. Protein kinase c activity blocks neuropeptide y-mediated inhibition of glutamate release and contributes to excitability of the hippocampus in status epilepticus. Faseb Journal, 2007, 21(3):671-681.
19.	Sheng H, Zhang Y, Sun J, et al. Corticotropin-releasing hormone (CRH) depresses n-methyl-d-aspartate receptor-mediated current in cultured rat hippocampal neurons via CRH receptor type 1. Endocrinology, 2008, 149(5):1389-1398.
20.	Hu GY, Hvalby O, Walaas SI, et al. Protein kinase c injection into hippocampal pyramidal cells elicits features of long term potentiation. Nature, 1987, 328(9):426-429.
21.	Takuma K, Matsuda T, Yoshikawa T, et al. Corticotropin-releasing factor stimulates Ca²⁺ influx in cultured rat astrocytes. Biochemical and Biophysical Research Communications, 1994, 199(10):1103-1107.
22.	Ha BK, Bishop GA, King JS, et al. Corticotropin releasing factor induces proliferation of cerebellar astrocytes. J Neurosci Res, 2000, 62(2):789-798.
23.	Ock J, Lee H, Kim S, et al. Induction of microglial apoptosis by corticotropin-releasing hormone. Journal of Neurochemistry, 2006, 98(2):962-972.
24.	Yang Y, Hahm E, Kim Y, et al. Regulation of IL-18 expression by CRH in mouse microglial cells. Immunol Lett, 2005, 98(1):291-296.
25.	Wang W, Ji P, Dow KE. Corticotropin-releasing hormone induces proliferation and TNF-alpha release in cultured rat microglia via MAP kinase signalling pathways. Journal of Neurochemistry, 2003, 84(5):189-195.

1. Sorel L, Dusaucy-Bauloye A. Findings in 21 cases of Gibbs' hypsarrhythmia; spectacular effectiveness of ACTH. Acta Neurol Psychiatr Belg, 1958, 58(7):130-141.
2. Baram TZ, Mitchell WG, Hanson RA, et al. Cerebrospinal fluid corticotropin and cortisol are reduced in infantile spasms. Pediatr Neurol, 1995, 13(4):108-110.
3. Brunson KL, Khan N, Eghbal-Ahmadi M, et al. Corticotropin (ACTH) acts directly on amygdala neurons to down-regulate corticotropin-releasing hormone gene expression. Ann Neurol, 2001, 49(5):304-312.
4. Brunson KL, Eghbal-Ahmadi M, Baram TZ. How do the many etiologies of West syndrome lead to excitability and seizures? The corticotropin releasing hormone excess hypothesis. Brain & Development, 2001, 23(10):533-538.
5. Lovenberg TW, Liaw CW, Grigoriadis DE, et al. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proceedings of the National Academy of Sciences of the United States of America, 1995, 92(7):836-840.
6. Grammatopoulos DK, Chrousos GP. Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends in Endocrinology and Metabolism, 2002, 13(6):436-444.
7. Grabaliskas G, Chapman H, Wheal HV. Role of protein kinase c in modulation of excitability of CA1 pyramidal neurons in the rat. Neuroscience, 2006, 139(4):1301-1313.
8. Asano E, Chugani DC, Juhasz C, et al. Surgical treatment of west syndrome. Brain Dev, 2001, 23(10):668-676.
9. Hollrigel GS, Chen K, Baram TZ, et al. The pro-convulsant actions of corticotropin-releasing hormone in the hippocampus of infant rats. Neuroscience, 1998, 84(2):71-79.
10. Baram TZ, Hatalski CG. Neuropeptide-mediated excitability:a key triggering mechanism for seizure generation in the developing brain. Trends in neurosciences, 1998, 21(3):471-476.
11. Aldenhoff JB, Gruol DL, Rivier J, et al. Corticotropin releasing factor decreases postburst hyperpolarizations and excites hippocampal neurons. Science (New York, N.Y.), 1983, 221(7):875-857.
12. Wang W, Dow KE, Fraser DD. Elevated corticotropin releasing hormone/corticotropin releasing hormone-R1 expression in postmortem brain obtained from children with generalized epilepsy. Annals of Neurology, 2001, 50(2):404-409.
13. Galanopoulou AS. Basic mechanisms of catastrophic epilepsy-overview from animal models. Brain & Development, 2013, 35(8):748-756.
14. Baram TZ, Chalmers DT, Chen C, et al. The CRF1 receptor mediates the excitatory actions of corticotropin releasing factor (CRF) in the developing rat brain:in vivo evidence using a novel, selective, non-peptide CRF receptor antagonist. Brain Research, 1997, 770(8):89-95.
15. Wang XD, Rammes G, Kraev I, et al. Forebrain CRF (1) modulates early-life stress-programmed cognitive deficits. J Neurosci, 2011, 31(11):13625-13634.
16. Brunson KL, Grigoriadis DE, Lorang MT, et al. Corticotropin-releasing hormone (CRH) downregulates the function of its receptor (CRF1) and induces CRF1 expression in hippocampal and cortical regions of the immature rat brain. Exp Neurol, 2002, 176(4):75-86.
17. Blank T, Nijholt I, Grammatopoulos DK, et al. Corticotropin-releasing factor receptors couple to multiple G-proteins to activate diverse intracellular signaling pathways in mouse hippocampus:role in neuronal excitability and associative learning. J Neurosci, 2003, 23(6):700-707.
18. Silva AP, Lourenco J, Xapelli S, et al. Protein kinase c activity blocks neuropeptide y-mediated inhibition of glutamate release and contributes to excitability of the hippocampus in status epilepticus. Faseb Journal, 2007, 21(3):671-681.
19. Sheng H, Zhang Y, Sun J, et al. Corticotropin-releasing hormone (CRH) depresses n-methyl-d-aspartate receptor-mediated current in cultured rat hippocampal neurons via CRH receptor type 1. Endocrinology, 2008, 149(5):1389-1398.
20. Hu GY, Hvalby O, Walaas SI, et al. Protein kinase c injection into hippocampal pyramidal cells elicits features of long term potentiation. Nature, 1987, 328(9):426-429.
21. Takuma K, Matsuda T, Yoshikawa T, et al. Corticotropin-releasing factor stimulates Ca²⁺ influx in cultured rat astrocytes. Biochemical and Biophysical Research Communications, 1994, 199(10):1103-1107.
22. Ha BK, Bishop GA, King JS, et al. Corticotropin releasing factor induces proliferation of cerebellar astrocytes. J Neurosci Res, 2000, 62(2):789-798.
23. Ock J, Lee H, Kim S, et al. Induction of microglial apoptosis by corticotropin-releasing hormone. Journal of Neurochemistry, 2006, 98(2):962-972.
24. Yang Y, Hahm E, Kim Y, et al. Regulation of IL-18 expression by CRH in mouse microglial cells. Immunol Lett, 2005, 98(1):291-296.
25. Wang W, Ji P, Dow KE. Corticotropin-releasing hormone induces proliferation and TNF-alpha release in cultured rat microglia via MAP kinase signalling pathways. Journal of Neurochemistry, 2003, 84(5):189-195.

Journal of Epilepsy

Expression of corticotropin releasing hormone and its receptors in infantile spasm

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