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2016 | 76 | 3 |

Tytuł artykułu

Aberrant changes of somatostatin and neuropeptide Y in brain of a genetic rat model for epilepsy: tremor rat

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Języki publikacji



Excessive excitation or loss of inhibitory neurotransmission has been closely related to epileptic activity. Somatostatin (SST) and Neuropeptide Y (NPY) are members of endogenous neuropeptides which are recognized as important modulator of classical neurotransmitter, distributed abundantly in mammalian central nervous system. Abnormal expression of these two neuropeptides evidenced in some epileptic models highlights the relevance of SST or NPY in the pathogenesis of epilepsy. The tremor rat (TRM) is a genetic epileptic animal model which can manifest tonic convulsions without any external stimuli. The present study aimed to investigate the distribution and expression of SST and NPY in TRM brains, including hippocampus, temporal lobe cortex and cerebellum. Our RT‑PCR data showed that up‑regulated mRNA expression of SST and NPY was discovered in TRM hippocampus and temporal lobe cortex compared with control (Wistar) rats. The peptide levels of these neuropeptides in brain areas mentioned above were both apparently higher than that in normal Wistar rats as well. However, in cerebellums, neither SST nor NPY was significantly changed compared with control group. The immunohistochemical data showed that SST and NPY were widely present throughout CA1, CA3 and the hilus of hippocampus, the entorhinal cortex of temporal lobe cortex, as well as cerebellar Purkinje layer. In conclusion, our results discovered the aberrant changes of SST and NPY in several TRM brain regions, suggesting that the peptidergic system might be involved in TRM epileptiform activity.

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Opis fizyczny



  • Department of Neurology, First Hospital of China Medical University, Shenyang, China
  • Institute of Neurology, China Medical University, Shenyang, China
  • Department of Pharmaceutical Toxicology, School of Pharmaceutical Science, China Medical University, Shenyang, China
  • Central Lab, the First Hospital of China Medical University, Shenyang, China
  • Department of Neurology, First Hospital of China Medical University, Shenyang, China
  • Institute of Neurology, China Medical University, Shenyang, China
  • Department of Neurology, First Hospital of China Medical University, Shenyang, China
  • Institute of Neurology, China Medical University, Shenyang, China
  • Experiment Center of Traditional Chinese Medicine, Affiliated Hospital, Liaoning University of Traditional Chinese Medicine, Shenyang, China
  • Department of Pharmaceutical Toxicology, School of Pharmaceutical Science, China Medical University, Shenyang, China
  • Department of Pharmaceutical Toxicology, School of Pharmaceutical Science, China Medical University, Shenyang, China


  • Baraban SC, Tallent MK (2004) Interneuron diversity series: interneuronal neuropeptides – endogenous regulators of neuronal excitability. Trends Neurosci 27: 135–142.
  • Boop S, Wheless J, Van Poppel K, McGregor A, Boop FA (2013) Cerebellar seizures. J Neurosurg Pediatr 12: 288–292.
  • Buckmaster PS, Dudek FE (1997) Neuron loss, granule cell axon reorganization, and functional changes in the dentate gyrus of epileptic kainate‑treated rats. J Comp Neurol 385: 385–404.
  • Buckmaster PS, Otero‑Corchon V, Rubinstein M, Low MJ (2002) Heightened seizure severity in somatostatin knockout mice. Epilepsy Res 48: 43–56.
  • Calik M, Ciftci A, Sarikaya S, Kocaturk O, Abuhandan M, Taskin A, Kandemir  H, Yoldas TK, Aksoy N (2015) Assessment of both serum S‑100B protein and neuropeptide‑Y levels in childhood breath‑holding spells. Epilepsy Behav 47: 34–38.
  • Cardoso A, Freitas‑da‑Costa P, Carvalho LS, Lukoyanov NV (2010) Seizure‑ ‑induced changes in neuropeptide Y‑containing cortical neurons: Potential role for seizure threshold and epileptogenesis. Epilepsy Behav 19: 559–567.
  • Choi YS, Lin SL, Lee B, Kurup P, Cho HY, Naegele JR, Lombroso PJ, Obrietan  K (2007) Status epilepticus-induced somatostatinergic hilar interneuron degeneration is regulated by striatal enriched protein tyrosine phosphatase. J Neurosci 27: 2999–3009.
  • 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.
  • Corvino V, Marchese E, Giannetti S, Lattanzi W, Bonvissuto D, Biamonte F, Mongiovì AM, Michetti F, Geloso MC (2012) The neuroprotective and neurogenic effects of neuropeptide Y administration in an animal model of hippocampal neurodegeneration and temporal lobe epilepsy induced by trimethyltin. J Neurochem 122: 415–426.
  • Corvino V, Marchese E, Podda MV, Lattanzi W, Giannetti S, Di Maria V, Cocco S, Grassi C, Michetti F, Geloso MC (2014) The neurogenic effects of exogenous neuropeptide Y: early molecular events and long-lasting effects in the hippocampus of trimethyltin‑treated rats. PLoS One 9: e88294.
  • 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.
  • de Lanerolle NC, Kim JH, Robbins RJ, Spencer DD (1989) Hippocampal interneuron loss and plasticity in human temporal lobe epilepsy. Brain Res 495: 387–395.
  • Dinocourt C, Petanjek Z, Freund TF, Ben‑Ari Y, Esclapez M (2003) Loss of interneurons innervating pyramidal cell dendrites and axon initial segments in the CA1 region of the hippocampus following pilocarpine‑induced seizures. J Comp Neurol 459: 407–425.
  • Drexel M, Kirchmair E, Wieselthaler‑Hölzl A, Preidt AP, Sperk G (2012) Somatostatin and neuropeptide Y neurons undergo different plasticity in parahippocampal regions in kainic acid‑induced epilepsy. J Neuropathol Exp Neurol 71: 312–329.
  • Dubé C, Brunson KL, Eghbal‑Ahmadi M, Gonzalez‑Vega R, Baram TZ (2005) Endogenous neuropeptide Y prevents recurrence of experimental febrile seizures by increasing seizure threshold. J Mol Neurosci 25: 275–284.
  • Erfanparast A, Tamaddonfard E (2015) Effects of intracortical microinjection of vitamin B12 on penicillin‑induced epileptiform activity in rats. Acta Neurobiol Exp (Wars) 75(2): 200–207.
  • Goto EM, Silva Mde P, Perosa SR, Argañaraz GA, Pesquero JB, Cavalheiro EA, Naffah-Mazzacoratti MG, Teixeira VP, Silva JA Jr (2010) Akt pathway activation and increased neuropeptide Y mRNA expression in the rat hippocampus: implications for seizure blockade. Neuropeptides 44: 169–176.
  • Guo F, Xu X, Cai J, Hu H, Sun W, He G, Shao D, Wang L, Chen T, Shaw C, Zhu T, Hao L (2013) The up‑regulation of voltage‑gated sodium channels subtypes coincides with an increased sodium current in hippocampal neuronal culture model. Neurochem Int 62: 287–295.
  • Hanaya R, Sasa M, Sugata S, Tokudome M, Serikawa T, Kurisu K, Arita K (2010) Hippocampal cell loss and propagation of abnormal discharges accompanied with the expression of tonic convulsion in the spontaneously epileptic rat. Brain Res 1328: 171–180.
  • Hashimoto T, Obata K (1991) Induction of somatostatin by kainic acid in pyramidal and granule cells of the rat hippocampus. Neurosci Res 12: 514–527.
  • Husum H, Bolwig TG, Sánchez C, Mathé AA, Hansen SL (2004) Levetiracetam prevents changes in levels of brain‑derived neurotrophic factor and neuropeptide Y mRNA and of Y1‑ and Y5‑like receptors in the hippocampus of rats undergoing amygdala kindling: implications for antiepileptogenic and mood‑stabilizing properties. Epilepsy Behav 5: 204–215.
  • Kokaia M (2011) Seizure‑induced neurogenesis in the adult brain. Eur J Neurosci 33: 1133–1138.
  • Kondo A, Nagara H, Akazawa K, Tateishi J, Serikawa T, Yamada J (1991) CNS Pathology in the neurological mutant rats zitter, tremor and zitter‑tremor double mutant (spontaneously epileptic rat, SER). Exaggeration of clinical and neuropathological phenotypes in SER. Brain 114: 979–999.
  • Kovac S, Walker MC (2013) Neuropeptides in epilepsy. Neuropeptides 47: 467–475.
  • Kozhemyakin M, Rajasekaran K, Todorovic MS, Kowalski SL, Balint C, Kapur J (2013) Somatostatin type‑2 receptor activation inhibits glutamate release and prevents status epilepticus. Neurobiol Dis 54: 94–104.
  • Li Y, Du H, Xie B, Wu N, Wang J, Wu G, Feng H, Jiang T (2010) Cerebellum abnormalities in idiopathic generalized epilepsy with generalized tonic-clonic seizures revealed by diffusion tensor imaging. PLoS One 5: e15219.
  • Lv X, Guo F, Xu X, Chen Z, Sun X, Min D, Cao Y, Shi X, Wang L, Chen T, Shaw  C, Gao H, Hao L, Cai J (2015) Abnormal alterations in the Ca2+/ CaV1.2/calmodulin/caMKII signaling pathway in a tremor rat model and in cultured hippocampal neurons exposed to Mg2+‑free solution. Mol Med Rep 12(5): 6663–6671, doi: 10.3892/mmr.2015.4227.
  • Madsen KK, Clausen RP, Larsson OM, Krogsgaard‑Larsen P, Schousboe A, White HS (2009) Synaptic and extrasynaptic GABA transporters as targets for anti‑epileptic drugs. J Neurochem 1: 139–144.
  • Mao X, Cao Y, Min D, Guo F, Xie N, Chen T, Shaw C, Cai J (2011b) RP-LC with fluorescence detection of amino acids in rat brain synaptosomes. Chromatographia 73: 157–163.
  • Mao X, Ma P, Cao D, Sun C, Ji Z, Min D, Sun H, Xie N, Cai J, Cao Y (2011a) Altered expression of GABAA receptors (α4, γ2 subunit), potassium chloride cotransporter 2 and astrogliosis in tremor rat hippocampus. Brain Res Bull 86 : 373–379.
  • Meurs A, Portelli J, Clinckers R, Balasubramaniam A, Michotte Y, Smolders I (2012) Neuropeptide Y increases in vivo hippocampal extracellular glutamate levels through Y1 receptor activation. Neurosci Lett 510: 143–147.
  • Mikkelsen JD, Woldbye DP (2006) Accumulated increase in neuropeptide Y and somatostatin gene expression of the rat in response to repeated electroconvulsive stimulation. J Psychiatr Res 40: 153–159.
  • Nadler JV, Tu B, Timofeeva O, Jiao Y, Herzog H (2007) Neuropeptide Y in the recurrent mossy fiber pathway. Peptides 28: 357–364.
  • 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.
  • Nagaki S, Nagak S, Minatogawa Y, Sadamatsu M, Kato N, Osawa M, Fukuyama Y (1996) The role of vasopressin, somatostatin and GABA in febrile convulsion in rat pups. Life Sci 58: 2233–2242.
  • Noé F, Frasca A, Balducci C, Carli M, Sperk G, Ferraguti F, Pitkänen A, Bland R, Fitzsimons H, During M, Vezzani A (2009) Neuropeptide Y overexpression using recombinant adeno‑associated viral vectors. Neurotherapeutics 6: 300–306.
  • Noé F, Nissinen J, Pitkänen A, Gobbi M, Sperk G, During M, Vezzani A (2007) Gene therapy in epilepsy: the focus on NPY. Peptides 28: 377–383.
  • Peineau S, Potier B, Petit F, Dournaud P, Epelbaum J, Gardette R (2003) AMPA‑sst2 somatostatin receptor interaction in rat hypothalamus requires activation of NMDA and/or metabotropic glutamate receptors and depends on intracellular calcium. J Physiol 546: 101–117.
  • Rijkers K, Moers-Hornikx VM, Hemmes RJ, Aalbers MW, Temel Y, Vles JS, Hoogland G (2015) Sustained Reduction of Cerebellar Activity in Experimental Epilepsy. Biomed Res Int: 718591.
  • Sadamatsu M, Kanai H, Masui A, Serikawa T, Yamada J, Sasa M, Kato N (1995). Altered brain contents of neuropeptides in spontaneously epileptic rats (SER) and tremor rats with absence seizures. Life Sci 57: 523–531.
  • Schwarzer C, Sperk G, Samanin R, Rizzi M, Gariboldi M, Vezzani A (1996) Neuropeptides‑immunoreactivity and their mRNA expression in kindling: functional implications for limbic epileptogenesis. Brain Res Brain Res Rev 22: 27–50.
  • Serikawa T, Ohno Y, Sasa M, Yamada J, Takaori S (1987) A new model of epilepsy: spontaneous spike and wave discharges in tremor rats. Lab Anim 21: 68–71.
  • Sloviter RS (1987) Decreased hippocampal inhibition and a selective loss of interneurons in experimental epilepsy. Science 235: 73–76.
  • Sperk G, Hamilton T, Colmers WF (2007) Neuropeptide Y in the dentate gyrus. Prog Brain Res 163: 285–297.
  • Striano P, Louis ED, Manto M (2013) Autosomal dominant cortical tremor, myoclonus, and epilepsy: is the origin in the cerebellum? Cerebellum 12: 145–146.
  • Tallent MK, Qiu C (2008) Somatostatin: an endogenous antiepileptic. Mol Cell Endocrinol 286: 96–103.
  • Vezzani A, Hoyer D (1999) Brain somatostatin: a candidate inhibitory role in seizures and epileptogenesis. Eur J Neurosci 11: 3767–3776.
  • Wang SJ (2005) Activation of neuropeptide Y Y1 receptors inhibits glutamate release through reduction of voltage‑dependent Ca2+ entry in the rat cerebral cortex nerve terminals: suppression of this inhibitory effect by the protein kinase C‑dependent facilitatory pathway. Neuroscience 134: 987–1000.
  • Wanscher B, Kragh J, Barry DI, Bolwig T, Zimmer J (1990) Increased somatostatin and enkephalin‑like immunoreactivity in the rat hippocampus following hippocampal kindling. Neurosci Lett 118: 33–36.
  • Weaver DF, Pohlmann‑Eden B (2013) Pharmacoresistant epilepsy: unmet needs in solving the puzzle(s). Epilepsia 54: 80–85.
  • Xu X, Guo F, He Q, Cai X, Min D, Wang Q, Wang S, Tian L, Cai J, Zhao Y (2014) Altered expression of neuropeptide Y, Y1 and Y2 receptors, but not Y5 receptor, within hippocampus and temporal lobe cortex of tremor rats. Neuropeptides 48: 97–105.
  • Xu X, Guo F, Lv X, Feng R, Min D, Ma L, Liu Y, Zhao J, Wang L, Chen T, Shaw C, Hao L, Cai J (2013) Abnormal changes in voltage‑gated sodium channels NaV1.1, NaV1.2, NaV1.3, NaV1.6 and in calmodulin/calmodulin‑dependent protein kinase II, within the brains of spontaneously epileptic rats and tremor rats. Brain Res Bull 96: 1–9.
  • Zafar R, King MA, Carney PR (2012) Adeno associated viral vector‑mediated expression of somatostatin in rat hippocampus suppresses seizure development. Neurosci Lett 509: 87–91.

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