In vivo blockade of ovarian sympathetic activity by Neosaxitoxin prevents polycystic ovary in rats

in Journal of Endocrinology
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  • 1 Laboratorio Bioquímica de Membrana, Departamento de Fisiología y Biofísica de la Facultad de Medicina de la Universidad de Chile, Santiago, Chile
  • 2 Centre for Neurobiochemical Studies on Endocrine Diseases, Laboratory of Neurobiochemistry, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, Universidad de Chile, Santiago de Chile, Chile

Correspondence should be addressed to H E Lara: hlara@ciq.uchile.cl
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A high sympathetic tone is observed in the development and maintenance of the polycystic ovary (PCO) phenotype in rats. Neosaxitoxin (NeoSTX) specifically blocks neuronal voltage-dependent Na+ channels, and we studied the capacity of NeoSTX administered into the ovary to block sympathetic nerves and PCO phenotype that is induced by estradiol valerate (EV). The toxin was administered with a minipump inserted into the bursal cavity using two protocols: (1) the same day as EV administration and (2) 30 days after EV to block the final step of cyst development and maintenance of the condition. We studied the estrous cycling activity, follicular morphology, steroid plasma levels, and norepinephrine concentration. NeoSTX administered together with EV decreased NA intraovarian levels that were induced by EV, increased the number of corpora lutea, decreased the number of follicular cyst found after EV administration, and decreased the previously increased testosterone plasma levels induced by the PCO phenotype. Estrous cycling activity also recovered. NeoSTX applied after 30 days of EV administration showed near recovery of ovary function, suggesting that there is a specific window in which follicular development could be protected from cystic development. In addition, plasma testosterone levels decreased while those of progesterone increased. Our data strongly suggest that chronic inhibition of sympathetic nerves by a locally applied long-lasting toxin is a new tool to manage the polycystic phenotype in the rat and could be applied to other mammals depending on sympathetic nerve activity.

 

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  • Alonso E, Alfonso A, Vieytes MR & Botana LM 2016 Evaluation of toxicity equivalent factors of paralytic shellfish poisoning toxins in seven human sodium channels types by an automated high throughput electrophysiology system. Archives of Toxicology 479488. (https://doi.org/10.1007/s00204-014-1444-y)

    • Search Google Scholar
    • Export Citation
  • Banaszewska B, Pawelczyk L & Spaczynski R 2019 Current and future aspects of several adjunctive treatment strategies in polycystic ovary syndrome. Reproductive Biology 309315. (https://doi.org/10.1016/j.repbio.2019.09.006)

    • Search Google Scholar
    • Export Citation
  • Barria A, Leyton V, Ojeda SR & Lara HE 1993 Ovarian steroidal response to gonadotropins and beta-adrenergic stimulation is enhanced in polycystic ovary syndrome: role of sympathetic innervation. Endocrinology 26962703. (https://doi.org/10.1210/endo.133.6.8243293)

    • Search Google Scholar
    • Export Citation
  • Birmingham K, Gradinaru V, Anikeeva P, Grill WM, Pikov V, Mclaughlin B, Pasricha P, Weber D, Ludwig K & Famm K 2014 Bioelectronic medicines: a research roadmap. Nature Reviews: Drug Discovery 399400. (https://doi.org/10.1038/nrd4351)

    • Search Google Scholar
    • Export Citation
  • Bulling A, Berg FD, Berg U, Duffy DM, Stouffer RL, Ojeda SR, Gratzl M & Mayerhofer A 2000 Identification of an ovarian voltage-activated Na+-channel type: hints to involvement in luteolysis. Molecular Endocrinology 10641074. (https://doi.org/10.1210/mend.14.7.0481)

    • Search Google Scholar
    • Export Citation
  • Burden HW, Lawrence IE Jr & Louis T 1985 The adrenergic innervation of the guinea pig ovary during prenatal and postnatal periods. Cells, Tissues, Organs 193196.

    • Search Google Scholar
    • Export Citation
  • Caldwell JH, Schaller KL, Lasher RS, Peles E & Levinson SR 2000 Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. PNAS 56165620. (https://doi.org/10.1073/pnas.090034797)

    • Search Google Scholar
    • Export Citation
  • Chavan SS & Tracey KJ 2017 Essential neuroscience in immunology. Journal of Immunology 33893397. (https://doi.org/10.4049/jimmunol.1601613)

    • Search Google Scholar
    • Export Citation
  • Chen H & Lim CED 2019 The efficacy of using acupuncture in managing polycystic ovarian syndrome. Current Opinion in Obstetrics and Gynecology 428432. (https://doi.org/10.1097/GCO.0000000000000582)

    • Search Google Scholar
    • Export Citation
  • Cruz G, Barra R, Gonzalez D, Sotomayor-Zarate R & Lara HE 2012 Temporal window in which exposure to estradiol permanently modifies ovarian function causing polycystic ovary morphology in rats. Fertility and Sterility 12831290. (https://doi.org/10.1016/j.fertnstert.2012.07.1060)

    • Search Google Scholar
    • Export Citation
  • Curry TE, Lawrence IE & Burden HW 1985 Ovarian sympathectomy in the golden hamster: effects on estrous cyclicity and follicular development. Experimental and Clinical Endocrinology 284290. (https://doi.org/10.1055/s-0029-1210498)

    • Search Google Scholar
    • Export Citation
  • Del Campo M, Piquer B, Witherington J, Sridhar A & Lara HE 2019 Effect of superior ovarian nerve and plexus nerve sympathetic denervation on ovarian-derived infertility provoked by estradiol exposure to rats. Frontiers in Physiology 349. (https://doi.org/10.3389/fphys.2019.00349)

    • Search Google Scholar
    • Export Citation
  • Dissen GA, Hill DF, Costa ME, Les Dees CW, Lara HE & Ojeda SR 1996 A role for trkA nerve growth factor receptors in mammalian ovulation. Endocrinology 198209. (https://doi.org/10.1210/endo.137.1.8536613)

    • Search Google Scholar
    • Export Citation
  • Dorfman M, Arancibia S, Fiedler JL & Lara HE 2003 Chronic intermittent cold stress activates ovarian sympathetic nerves and modifies ovarian follicular development in the rat. Biology of Reproduction 20382043. (https://doi.org/10.1095/biolreprod.102.008318)

    • Search Google Scholar
    • Export Citation
  • Flores A, Velasco J, Gallegos AI, Mendoza FD, Everardo PM, Cruz ME & Dominguez R 2011 Acute effects of unilateral sectioning the superior ovarian nerve of rats with unilateral ovariectomy on ovarian hormones (progesterone, testosterone and estradiol) levels vary during the estrous cycle. Reproductive Biology and Endocrinology 34. (https://doi.org/10.1186/1477-7827-9-34)

    • Search Google Scholar
    • Export Citation
  • Garcia C, Perez F, Contreras C, Figueroa D, Barriga A, Lopez-Rivera A, Araneda OF & Contreras HR 2015 Saxitoxins and okadaic acid group: accumulation and distribution in invertebrate marine vectors from Southern Chile. Food Additives and Contaminants: Part A, Chemistry, Analysis, Control, Exposure and Risk Assessment 9841002. (https://doi.org/10.1080/19440049.2015.1028107)

    • Search Google Scholar
    • Export Citation
  • Greiner M, Paredes A, Araya V & Lara HE 2005 Role of stress and sympathetic innervation in the development of polycystic ovary syndrome. Endocrine 319324. (https://doi.org/10.1385/ENDO:28:3:319)

    • Search Google Scholar
    • Export Citation
  • Grisk O 2020 The sympathetic nervous system in acute kidney injury. Acta Physiologica e13404. (https://doi.org/10.1111/apha.13404)

  • Jacobowitz D & Wallach EE 1967 Histochemical and chemical studies of the autonomic innervation of the ovary. Endocrinology 11321139. (https://doi.org/10.1210/endo-81-5-1132)

    • Search Google Scholar
    • Export Citation
  • Kuang HY, Li Y, Zhang HP, Legro RS & Stener-Victorin E 2018 Data do not support effectiveness of acupuncture for improving live birth rate in women with polycystic ovary syndrome. Chinese Journal of Integrative Medicine 399400. (https://doi.org/10.1007/s11655-018-2842-4)

    • Search Google Scholar
    • Export Citation
  • Lansdown A & Rees DA 2012 The sympathetic nervous system in polycystic ovary syndrome: a novel therapeutic target? Clinical Endocrinology 791801. (https://doi.org/10.1111/cen.12003)

    • Search Google Scholar
    • Export Citation
  • Lara H, Galleguillos X, Arrau J & Belmar J 1985 Effect of castration and testosterone on norepinephrine storage and on the release of [(3)H]norepinephrine from rat vas deferens. Neurochemistry International 667674. (https://doi.org/10.1016/0197-0186(85)90064-6)

    • Search Google Scholar
    • Export Citation
  • Lara HE, Mcdonald JK, Ahmed CE & Ojeda SR 1990a Guanethidine-mediated destruction of ovarian sympathetic nerves disrupts ovarian development and function in rats. Endocrinology 21992209. (https://doi.org/10.1210/endo-127-5-2199)

    • Search Google Scholar
    • Export Citation
  • Lara HE, Mcdonald JK & Ojeda SR 1990b Involvement of nerve growth factor in female sexual development. Endocrinology 364375. (https://doi.org/10.1210/endo-126-1-364)

    • Search Google Scholar
    • Export Citation
  • Lara HE, Ferruz JL, Luza S, Bustamante DA, Borges Y & Ojeda SR 1993 Activation of ovarian sympathetic nerves in polycystic ovary syndrome. Endocrinology 26902695. (https://doi.org/10.1210/endo.133.6.7902268)

    • Search Google Scholar
    • Export Citation
  • Lara HE, Dissen GA, Leyton V, Paredes A, Fuenzalida H, Fiedler JL & Ojeda SR 2000 An increased intraovarian synthesis of nerve growth factor and its low affinity receptor is a principal component of steroid-induced polycystic ovary in the rat. Endocrinology 10591072. (https://doi.org/10.1210/endo.141.3.7395)

    • Search Google Scholar
    • Export Citation
  • Lara HE, Dorfman M, Venegas M, Luza SM, Luna SL, Mayerhofer A, Guimaraes MA, Rosa E Silva AA & Ramirez VD 2002 Changes in sympathetic nerve activity of the mammalian ovary during a normal estrous cycle and in polycystic ovary syndrome: studies on norepinephrine release. Microscopy Research and Technique 495502. (https://doi.org/10.1002/jemt.10229)

    • Search Google Scholar
    • Export Citation
  • Lawrence IE & Burden HW 1980 The origin of the extrinsic adrenergic innervation to the rat ovary. Anatomical Record 5159. (https://doi.org/10.1002/ar.1091960106)

    • Search Google Scholar
    • Export Citation
  • Lim CED, Ng RWC, Cheng NCL, Zhang GS & Chen H 2019 Acupuncture for polycystic ovarian syndrome. Cochrane Database of Systematic Reviews CD007689. (https://doi.org/10.1002/14651858.CD007689.pub4)

    • Search Google Scholar
    • Export Citation
  • Llewellyn LE 2006 Saxitoxin, a toxic marine natural product that targets a multitude of receptors. Natural Product Reports 200222. (https://doi.org/10.1039/b501296c)

    • Search Google Scholar
    • Export Citation
  • Lobo K, Donado C, Cornelissen L, Kim J, Ortiz R, Peake RW, Kellogg M, Alexander ME, Zurakowski D, Kurgansky KE, et al. 2015 A Phase 1, dose-escalation, double-blind, block-randomized, controlled trial of safety and efficacy of neosaxitoxin alone and in combination with 0.2% bupivacaine, with and without epinephrine, for cutaneous anesthesia. Anesthesiology 873885. (https://doi.org/10.1097/ALN.0000000000000831)

    • Search Google Scholar
    • Export Citation
  • Luna SL, Neuman S, Aguilera J, Brown DI & Lara HE 2012 In vivo beta-adrenergic blockade by propranolol prevents isoproterenol-induced polycystic ovary in adult rats. Hormone and Metabolic Research 676681. (https://doi.org/10.1055/s-0031-1301304)

    • Search Google Scholar
    • Export Citation
  • Manriquez V, Castro Caperan D, Guzman R, Naser M, Iglesia V & Lagos N 2015 First evidence of neosaxitoxin as a long-acting pain blocker in bladder pain syndrome. International Urogynecology Journal 853858. (https://doi.org/10.1007/s00192-014-2608-2)

    • Search Google Scholar
    • Export Citation
  • Marcondes FK, Bianchi FJ & Tanno AP 2002 Determination of the estrous cycle phases of rats: some helpful considerations. Brazilian Journal of Biology 609614. (https://doi.org/10.1590/s1519-69842002000400008)

    • Search Google Scholar
    • Export Citation
  • Neilson D, Jones GS, Woodruff JD & Goldberg B 1970 The innervation of the ovary. Obstetrical and Gynecological Survey 889904. (https://doi.org/10.1097/00006254-197010000-00001)

    • Search Google Scholar
    • Export Citation
  • Pastelin CF, Rosas NH, Morales-Ledesma L, Linares R, Dominguez R & Moran C 2017 Anatomical organization and neural pathways of the ovarian plexus nerve in rats. Journal of Ovarian Research 18. (https://doi.org/10.1186/s13048-017-0311-x)

    • Search Google Scholar
    • Export Citation
  • Pavlov VA & Tracey KJ 2017 Neural regulation of immunity: molecular mechanisms and clinical translation. Nature Neuroscience 156166. (https://doi.org/10.1038/nn.4477)

    • Search Google Scholar
    • Export Citation
  • Pikov V, Sridhar A & Lara HE 2018 High-frequency electrical modulation of the superior ovarian nerve as a treatment of polycystic ovary syndrome in the rat. Frontiers in Physiology 459. (https://doi.org/10.3389/fphys.2018.00459)

    • Search Google Scholar
    • Export Citation
  • Rathmell JP, Strichartz G & Wanderer J 2015 Neosaxitoxin versus traditional local anesthetics: mechanism of action and sites of notable effect. Anesthesiology A23. (https://doi.org/10.1097/01.anes.0000470956.02665.a6)

    • Search Google Scholar
    • Export Citation
  • Riquelme G, Sepulveda JM, Al Ghumgham Z, Del Campo M, Montero C & Lagos N 2018 Neosaxitoxin, a paralytic shellfish poison toxin, effectively manages bucked shins pain, as a local long-acting pain blocker in an equine model. Toxicon 1517. (https://doi.org/10.1016/j.toxicon.2017.11.004)

    • Search Google Scholar
    • Export Citation
  • Riquelme R, Ruz F, Mayerhofer A & Lara HE 2019 Role of ovarian sympathetic nerves and cholinergic local system during cold stress. Journal of Endocrinology 115124. (https://doi.org/10.1530/JOE-19-0125)

    • Search Google Scholar
    • Export Citation
  • Rodriguez-Navarro AJ, Lagos N, Lagos M, Braghetto I, Csendes A, Hamilton J, Figueroa C, Truan D, Garcia C, Rojas A, et al. 2007a Neosaxitoxin as a local anesthetic: preliminary observations from a first human trial. Anesthesiology 339345. (https://doi.org/10.1097/00000542-200702000-00023)

    • Search Google Scholar
    • Export Citation
  • Rodriguez-Navarro AJ, Saenz R & Navarrete C 2007b Esophageal stenosis in epidermolysis bullosa. Gastrointestinal Endoscopy 1067. (https://doi.org/10.1016/j.gie.2007.05.003)

    • Search Google Scholar
    • Export Citation
  • Rosas G, Linares R, Ramirez DA, Vieyra E, Trujillo A, Dominguez R & Morales-Ledesma L 2018 The neural signals of the superior ovarian nerve modulate in an asymmetric way the ovarian steroidogenic response to the vasoactive intestinal peptide. Frontiers in Physiology 1142. (https://doi.org/10.3389/fphys.2018.01142)

    • Search Google Scholar
    • Export Citation
  • Stener-Victorin E, Jedel E & Manneras L 2008 Acupuncture in polycystic ovary syndrome: current experimental and clinical evidence. Journal of Neuroendocrinology 290298. (https://doi.org/10.1111/j.1365-2826.2007.01634.x)

    • Search Google Scholar
    • Export Citation
  • Stener-Victorin E, Jedel E, Janson PO & Sverrisdottir YB 2009 Low-frequency electroacupuncture and physical exercise decrease high muscle sympathetic nerve activity in polycystic ovary syndrome. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology R387R395. (https://doi.org/10.1152/ajpregu.00197.2009)

    • Search Google Scholar
    • Export Citation
  • Toufexis D, Rivarola MA, Lara H & Viau V 2014 Stress and the reproductive axis. Journal of Neuroendocrinology 573586. (https://doi.org/10.1111/jne.12179)

    • Search Google Scholar
    • Export Citation
  • Uchida S & Kagitani F 2014 Effects of electrical stimulation of autonomic nerves to the ovary on the ovarian testosterone secretion rate in rats. Autonomic Neuroscience: Basic and Clinical 4852. (https://doi.org/10.1016/j.autneu.2013.10.007)

    • Search Google Scholar
    • Export Citation
  • Urra J, Blohberger J, Tiszavari M, Mayerhofer A & Lara HE 2016 In vivo blockade of acetylcholinesterase increases intraovarian acetylcholine and enhances follicular development and fertility in the rat. Scientific Reports 30129. (https://doi.org/10.1038/srep30129)

    • Search Google Scholar
    • Export Citation
  • Velasquez M, Fernandez L, Leib CS, Orozco V, Pava F & Perafan P 2019 Cardiac sympathetic denervation for conventional treatment refractory arrhythmias. Archivos de Cardiología de México 211215. (https://doi.org/10.24875/ACM.M19000052)

    • Search Google Scholar
    • Export Citation
  • Venegas B, De Leon Gordillo LY, Rosas G, Espinoza JA, Moran C, Dominguez R & Morales-Ledesma L 2019 In rats with estradiol valerate-induced polycystic ovary syndrome, the acute blockade of ovarian beta-adrenoreceptors improve ovulation. Reproductive Biology and Endocrinology 95. (https://doi.org/10.1186/s12958-019-0539-y)

    • Search Google Scholar
    • Export Citation
  • Wakade AR 1979 Recycling of noradrenergic storage vesicles of isolated rat vas deferens. Nature 374376. (https://doi.org/10.1038/281374a0)

    • Search Google Scholar
    • Export Citation
  • Wakade AR 1980 A maximum contraction and substantial quantities of tritium can be obtained from tetraethylammonium-treated [3H]-noradrenaline preloaded, rat vas deferens in response to a single electrical shock. British Journal of Pharmacology 425436. (https://doi.org/10.1111/j.1476-5381.1980.tb14556.x)

    • Search Google Scholar
    • Export Citation
  • Zamorano R, Marin M, Cabrera F, Figueroa D, Contreras C, Barriga A, Lagos N & Garcia C 2013 Determination of the variability of both hydrophilic and lipophilic toxins in endemic wild bivalves and carnivorous gastropods from the southern part of Chile. Food Additives and Contaminants: Part A, Chemistry, Analysis, Control, Exposure and Risk Assessment 16601677. (https://doi.org/10.1080/19440049.2013.805438)

    • Search Google Scholar
    • Export Citation
  • Zar JH 1984 Biostatistical Analysis. Englewood Cliffs, NJ: Prentice-HaIl.

  • Zheng Y, Stener-Victorin E, Ng EH, Li J, Wu X & Ma H 2015 How does acupuncture affect insulin sensitivity in women with polycystic ovary syndrome and insulin resistance? Study protocol of a prospective pilot study. BMJ Open e007757. (https://doi.org/10.1136/bmjopen-2015-007757)

    • Search Google Scholar
    • Export Citation