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Octreotide ameliorates inflammation and apoptosis in acute and kindled murine PTZ paradigms

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Abstract

In the present study, the role of octreotide (OCT) in pentylenetetrazole (PTZ) kindling as well as in acute convulsion models was evaluated. Mice were allocated in groups as (1) control saline; (2) acute PTZ (PTZ-a; 60 mg/kg, i.p.), as a single convulsive dose; and (3) kindled (PTZ-k) receiving nine subconvulsive doses of PTZ (40 mg/kg, i.p.) for 17 days. Groups 4–7 received either valproic acid (VPA) 50 mg/kg or OCT (50 μg/kg, Sandostatin®) 30 min by oral gavage before PTZ-a or PTZ-k. The median seizure stage, latency onset of first stage 4/5 seizures, and incidence of convulsing animals were recorded. Cortical dopamine (DA), tumor necrosis factor (TNF)-α, interleukin (IL)-10, caspase (Casp)-3, myeloperoxidase (MPO), and nitric oxide (NO) were assessed in addition to inducible nitric oxide synthase (iNOS) that was evaluated immunohistochemically in a different set of groups. OCT halted PTZ-induced epilepsy delaying convulsion latency via modulating MPO and TNF-α and normalizing IL-10 with both treatment regimens. In PTZ-k, it decreased Casp-3 activity, NO level, and iNOS immunoreactivity. OCT in both paradigms decreased DA concentration. The current investigation implicates a crucial role for OCT in modulating PTZ-induced kindling by regulating inflammatory and apoptotic effects.

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Abbreviations

Casp-3:

Caspase-3

DA:

Dopamine

iNOS:

Inducible nitric oxide synthase

IL-10:

Interleukin 10

MPO:

Myeloperoxidase

NO:

Nitric oxide

OCT:

Octreotide

PTZ:

Pentylenetetrazole

SRIF:

Somatotropin release-inhibiting factor

TNF-α:

Tumor necrosis factor

VPA:

Valproic acid

References

  • Abdallah DM (2010) Anticonvulsant potential of the peroxisome proliferator-activated receptor gamma agonist pioglitazone in pentylenetetrazole-induced acute seizures and kindling in mice. Brain Res 1351:246–253. doi:10.1016/j.brainres.2010.06.034

    Article  CAS  PubMed  Google Scholar 

  • Ammon-Treiber S, Grecksch G, Angelidis C, Vezyraki P, Hollt V, Becker A (2007) Pentylenetetrazol-kindling in mice overexpressing heat shock protein 70. Naunyn Schmiedebergs Arch Pharmacol 375:115–121. doi:10.1007/s00210-007-0143-0

    Article  CAS  PubMed  Google Scholar 

  • Avignone E, Ulmann L, Levavasseur F, Rassendren F, Audinat E (2008) Status epilepticus induces a particular microglial activation state characterized by enhanced purinergic signaling. J Neurosci 28:9133–9144. doi:10.1523/JNEUROSCI.1820-08.2008

    Article  CAS  PubMed  Google Scholar 

  • Bikjdaouene L, Escames G, Leon J, Ferrer JM, Khaldy H, Vives F, Acuna-Castroviejo D (2003) Changes in brain amino acids and nitric oxide after melatonin administration in rats with pentylenetetrazole-induced seizures. J Pineal Res 35:54–60

    Article  CAS  PubMed  Google Scholar 

  • Buckmaster PS, Otero-Corchon V, Rubinstein M, Low MJ (2002) Heightened seizure severity in somatostatin knockout mice. Epilepsy Res 48:43–56

    Article  CAS  PubMed  Google Scholar 

  • Chang CY, Song MJ, Jeon SB, Yoon HJ, Lee DK, Kim IH, Suk K, Choi DK, Park EJ (2011) Dual functionality of myeloperoxidase in rotenone-exposed brain-resident immune cells. Am J Pathol 179:964–979. doi:10.1016/j.ajpath.2011.04.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Wersinger C, Sidhu A (2003) Chronic stimulation of D1 dopamine receptors in human SK-N-MC neuroblastoma cells induces nitric-oxide synthase activation and cytotoxicity. J Biol Chem 278:28089–28100. doi:10.1074/jbc.M303094200

    Article  CAS  PubMed  Google Scholar 

  • Christensen KV, Leffers H, Watson WP, Sanchez C, Kallunki P, Egebjerg J (2010) Levetiracetam attenuates hippocampal expression of synaptic plasticity-related immediate early and late response genes in amygdala-kindled rats. BMC Neurosci 11:9. doi:10.1186/1471-2202-11-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Clynen E, Swijsen A, Raijmakers M, Hoogland G, Rigo JM (2014) Neuropeptides as targets for the development of anticonvulsant drugs. Mol Neurobiol 50:626–646. doi:10.1007/s12035-014-8669-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Csaba Z, Richichi C, Bernard V, Epelbaum J, Vezzani A, Dournaud P (2004) Plasticity of somatostatin and somatostatin sst2A receptors in the rat dentate gyrus during kindling epileptogenesis. Eur J Neurosci 19:2531–2538. doi:10.1111/j.0953-816X.2004.03361.x

    Article  PubMed  Google Scholar 

  • De LG, Di Giorgio RM, Macaione S, Calpona PR, Di Paola ED, Costa N, Cuzzocrea S, Citraro R, Russo E, De SG (2006) Amino acid levels in some brain areas of inducible nitric oxide synthase knock out mouse (iNOS-/-) before and after pentylenetetrazole kindling. Pharmacol Biochem Behav 85:804–812. doi:10.1016/j.pbb.2006.11.016

    Article  Google Scholar 

  • Dringen R, Pawlowski PG, Hirrlinger J (2005) Peroxide detoxification by brain cells. J Neurosci Res 79:157–165. doi:10.1002/jnr.20280

    Article  CAS  PubMed  Google Scholar 

  • El-Abhar HS, El Gawad HM (2003) Modulation of cortical nitric oxide synthase, glutamate, and redox state by nifedipine and taurine in PTZ-kindled mice. Epilepsia 44:276–281

    Article  CAS  PubMed  Google Scholar 

  • Fridley J, Thomas JG, Navarro JC, Yoshor D (2012) Brain stimulation for the treatment of epilepsy. Neurosurg Focus 32, E13. doi:10.3171/2012.1.FOCUS11334

    Article  PubMed  Google Scholar 

  • Gonzalez P, Burgaya F, Acarin L, Peluffo H, Castellano B, Gonzalez B (2009) Interleukin-10 and interleukin-10 receptor-I are upregulated in glial cells after an excitotoxic injury to the postnatal rat brain. J Neuropathol Exp Neurol 68:391–403. doi:10.1097/NEN.0b013e31819dca30

    Article  CAS  PubMed  Google Scholar 

  • Ichiyama T, Okada K, Lipton JM, Matsubara T, Hayashi T, Furukawa S (2000) Sodium valproate inhibits production of TNF-alpha and IL-6 and activation of NF-kappaB. Brain Res 857:246–251

    Article  CAS  PubMed  Google Scholar 

  • ILAR (1996) Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, DC

    Google Scholar 

  • Indra MR, Karyono S, Ratnawati R, Malik SG (2013) Quercetin suppresses inflammation by reducing ERK1/2 phosphorylation and NF kappa B activation in leptin-induced human umbilical vein endothelial cells (HUVECs). BMC Res Notes 6:275. doi:10.1186/1756-0500-6-275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Innamorato NG, Lastres-Becker I, Cuadrado A (2009) Role of microglial redox balance in modulation of neuroinflammation. Curr Opin Neurol 22:308–314. doi:10.1097/WCO.0b013e32832a3225

    Article  CAS  PubMed  Google Scholar 

  • Itoh K, Watanabe M, Yoshikawa K, Kanaho Y, Berliner LJ, Fujii H (2004) Magnetic resonance and biochemical studies during pentylenetetrazole-kindling development: the relationship between nitric oxide, neuronal nitric oxide synthase and seizures. Neuroscience 129:757–766. doi:10.1016/j.neuroscience.2004.09.025

    Article  CAS  PubMed  Google Scholar 

  • Khurgel M, Ivy GO (1996) Astrocytes in kindling: relevance to epileptogenesis. Epilepsy Res 26:163–175

    Article  CAS  PubMed  Google Scholar 

  • Kovac A, Zilkova M, Deli MA, Zilka N, Novak M (2009) Human truncated tau is using a different mechanism from amyloid-beta to damage the blood-brain barrier. J Alzheimers Dis 18:897–906. doi:10.3233/JAD-2009-1197

    CAS  PubMed  Google Scholar 

  • Krawisz JE, Sharon P, Stenson WF (1984) Quantitative assay for acute intestinal inflammation based on myeloperoxidase activity. Assessment of inflammation in rat and hamster models. Gastroenterology 87:1344–1350

    CAS  PubMed  Google Scholar 

  • Lang A, Sakhnini E, Fidder HH, Maor Y, Bar-Meir S, Chowers Y (2005) Somatostatin inhibits pro-inflammatory cytokine secretion from rat hepatic stellate cells. Liver Int 25:808–816. doi:10.1111/j.1478-3231.2005.01057.x

    Article  CAS  PubMed  Google Scholar 

  • Li J, Zhong W, Wang W, Hu S, Yuan J, Zhang B, Hu T, Song G (2014) Ginsenoside metabolite compound K promotes recovery of dextran sulfate sodium-induced colitis and inhibits inflammatory responses by suppressing NF-kappaB activation. PLoS One 9:e87810. doi:10.1371/journal.pone.0087810

    Article  PubMed  PubMed Central  Google Scholar 

  • LOWRY OH, ROSEBROUGH NJ, FARR AL, RANDALL RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Miranda KM, Espey MG, Wink DA (2001) A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide 5:62–71. doi:10.1006/niox.2000.0319

    Article  CAS  PubMed  Google Scholar 

  • Mishra J, Chaudhary T, Kumar A (2014) Rosiglitazone synergizes the neuroprotective effects of valproic acid against quinolinic acid-induced neurotoxicity in rats: targeting PPARgamma and HDAC pathways. Neurotox Res 26:130–151. doi:10.1007/s12640-014-9458-z

    Article  CAS  PubMed  Google Scholar 

  • Mohamed RA, Agha AM, Nassar NN (2012) SCH58261 the selective adenosine A(2A) receptor blocker modulates ischemia reperfusion injury following bilateral carotid occlusion: role of inflammatory mediators. Neurochem Res 37:538–547. doi:10.1007/s11064-011-0640-x

    Article  CAS  PubMed  Google Scholar 

  • Morimoto K, Fahnestock M, Racine RJ (2004) Kindling and status epilepticus models of epilepsy: rewiring the brain. Prog Neurobiol 73:1–60. doi:10.1016/j.pneurobio.2004.03.009

    Article  CAS  PubMed  Google Scholar 

  • Nagaki S, Fukamauchi F, Sakamoto Y, Higuchi H, Miki N, Miki N, Ono M, Sadamatsu M, Kato N, Osawa M (2000) Upregulation of brain somatostatin and neuropeptide Y following lidocaine-induced kindling in the rat. Brain Res 852:470–474

    Article  CAS  PubMed  Google Scholar 

  • Nagatomo I, Akasaki Y, Uchida M, Tominaga M, Hashiguchi W, Takigawa M (2000) Effects of combined administration of zonisamide and valproic acid or phenytoin to nitric oxide production, monoamines and zonisamide concentrations in the brain of seizure-susceptible EL mice. Brain Res Bull 53:211–218

    Article  CAS  PubMed  Google Scholar 

  • Nakken KO, Heuser K, Alfstad K, Tauboll E (2014) How do antiepileptic drugs work? Tidsskr Nor Laegeforen 134:42–46. doi:10.4045/tidsskr.13.0761

    Article  PubMed  Google Scholar 

  • Nassar NN, Schaalan MF, Zaki HF, Abdallah DM (2011) Octreotide ameliorates gastric lesions in chronically mild stressed rats. World J Gastroenterol 17:1135–1142. doi:10.3748/wjg.v17.i9.1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ou Y, Liu R, Wei N, Li X, Qiang O, Huang W, Tang C (2012) Effects of octreotide on nitric oxide synthase expression in the small intestine of high fat diet-induced obese rats. Obes Res Clin Pract 6:e263–e346. doi:10.1016/j.orcp.2011.11.004

    Article  PubMed  Google Scholar 

  • Paul V, Subramanian EH (2002) Evidence for an involvement of nitric oxide and gamma aminobutyric acid in the anticonvulsant action of L-arginine on picrotoxin-induced convulsions in rats. Pharmacol Biochem Behav 72:515–519

    Article  CAS  PubMed  Google Scholar 

  • Payandemehr B, Rahimian R, Gooshe M, Bahremand A, Gholizadeh R, Berijani S, Ahmadi-Dastgerdi M, Aminizade M, Sarreshte-Dari A, Dianati V, Amanlou M, Dehpour AR (2014) Nitric oxide mediates the anticonvulsant effects of thalidomide on pentylenetetrazole-induced clonic seizures in mice. Epilepsy Behav 34:99–104. doi:10.1016/j.yebeh.2014.03.020

    Article  PubMed  Google Scholar 

  • Peluso G, Petillo O, Melone MA, Mazzarella G, Ranieri M, Tajana GF (1996) Modulation of cytokine production in activated human monocytes by somatostatin. Neuropeptides 30:443–451

    Article  CAS  PubMed  Google Scholar 

  • Plata-Salaman CR, Ilyin SE, Turrin NP, Gayle D, Flynn MC, Romanovitch AE, Kelly ME, Bureau Y, Anisman H, McIntyre DC (2000) Kindling modulates the IL-1beta system, TNF-alpha, TGF-beta1, and neuropeptide mRNAs in specific brain regions. Brain Res Mol Brain Res 75:248–258

    Article  CAS  PubMed  Google Scholar 

  • Rao KM (2000) Molecular mechanisms regulating iNOS expression in various cell types. J Toxicol Environ Health B Crit Rev 3:27–58. doi:10.1080/109374000281131

    Article  CAS  PubMed  Google Scholar 

  • Schaalan MF, Nassar NN (2011) Effects of octreotide in chronically mild stressed rats: possible role of immune and oxidative stress pathways. Neurochem Res 36:1717–1723. doi:10.1007/s11064-011-0486-2

    Article  CAS  PubMed  Google Scholar 

  • Singhal G, Jaehne EJ, Corrigan F, Baune BT (2014) Cellular and molecular mechanisms of immunomodulation in the brain through environmental enrichment. Front Cell Neurosci 8:97. doi:10.3389/fncel.2014.00097

    Article  PubMed  PubMed Central  Google Scholar 

  • Stewart VC, Heales SJ (2003) Nitric oxide-induced mitochondrial dysfunction: implications for neurodegeneration. Free Radic Biol Med 34:287–303

    Article  CAS  PubMed  Google Scholar 

  • Szyndler J, Maciejak P, Turzynska D, Sobolewska A, Bidzinski A, Plaznik A (2010) Time course of changes in the concentrations of monoamines in the brain structures of pentylenetetrazole-kindled rats. J Neural Transm 117:707–718. doi:10.1007/s00702-010-0414-7

    Article  PubMed  Google Scholar 

  • Ter VF, Rose B, Rose B, Mussmann R, Martin S, Herder C, Kempf K (2009) Effects of somatostatin and octreotide on cytokine and chemokine production by lipopolysaccharide-activated peripheral blood mononuclear cells. J Endocrinol Invest 32:123–129

    Article  Google Scholar 

  • Uma DP, Pillai KK, Vohora D (2006) Modulation of pentylenetetrazole-induced seizures and oxidative stress parameters by sodium valproate in the absence and presence of N-acetylcysteine. Fundam Clin Pharmacol 20:247–253. doi:10.1111/j.1472-8206.2006.00401.x

    Article  Google Scholar 

  • Velasco-Ramirez SF, Rosales-Rivera LY, Ramirez-Anguiano AC, Bitzer-Quintero OK (2013) Cytokines and the nervous system: the relationship between seizures and epilepsy. Rev Neurol 57:171–177

    CAS  PubMed  Google Scholar 

  • Vezzani A, Granata T (2005) Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46:1724–1743. doi:10.1111/j.1528-1167.2005.00298.x

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Serafini R, Stasi MA, Vigano G, Rizzi M, Samanin R (1991) A peptidase-resistant cyclic octapeptide analogue of somatostatin (SMS 201-995) modulates seizures induced by quinolinic and kainic acids differently in the rat hippocampus. Neuropharmacology 30:345–352

    Article  CAS  PubMed  Google Scholar 

  • Vezzani A, Balosso S, Ravizza T (2008) The role of cytokines in the pathophysiology of epilepsy. Brain Behav Immun 22:797–803. doi:10.1016/j.bbi.2008.03.009

    Article  CAS  PubMed  Google Scholar 

  • Watanabe M, Miyai A, Danjo S, Nakamura Y, Itoh K (2013) The threshold of pentylenetetrazole-induced convulsive seizures, but not that of nonconvulsive seizures, is controlled by the nitric oxide levels in murine brains. Exp Neurol 247:645–652. doi:10.1016/j.expneurol.2013.02.019

    Article  CAS  PubMed  Google Scholar 

  • Zhou H, Gao J, Zou D, Wu W, Li Z (2012) Effect of octreotide on enteric motor neurons in experimental acute necrotizing pancreatitis. PLoS One 7, e52163. doi:10.1371/journal.pone.0052163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    M. Y. Al-Shorbagy & Noha N. Nassar

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  1. M. Y. Al-Shorbagy
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Correspondence to Noha N. Nassar.

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Al-Shorbagy, M.Y., Nassar, N.N. Octreotide ameliorates inflammation and apoptosis in acute and kindled murine PTZ paradigms. Naunyn-Schmiedeberg's Arch Pharmacol 390, 61–68 (2017). https://doi.org/10.1007/s00210-016-1303-x

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