Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences65156510.31857/S0869813923050059XQROOKEXPERIMENTAL ARTICLESЭКСПЕРИМЕНТАЛЬНЫЕ СТАТЬИThe Effect of Spinal Cord Injury on P2 Signaling in the Cholinergic SynapseВлияние травмы спинного мозга на Р2-сигнализацию в холинергическом синапсеKhairullinA. E.ХайруллинА. Е.khajrulli@yandex.ruEfimovaD. V.ЕфимоваД. В.khajrulli@yandex.ruEremeevA. A.ЕремеевА. А.khajrulli@yandex.ruSabirovaD. E.СабироваД. Э.khajrulli@yandex.ruGrishinS. N.ГришинС. Н.khajrulli@yandex.ruZiganshinA. U.ЗиганшинА. У.khajrulli@yandex.ruKazan State Medical UniversityКазанский государственный медицинский университетKazan Federal UniversityКазанский федеральный университет01052023109558859901022025Copyright ©; 2023, А.Е. Хайруллин, Д.В. Ефимова, А.А. Еремеев, Д.Э. Сабирова, С.Н. Гришин, А.У. ЗиганшинCopyright ©; 2023, А.Е. Хайруллин, Д.В. Ефимова, А.А. Еремеев, Д.Э. Сабирова, С.Н. Гришин, А.У. Зиганшин2023А.Е. Хайруллин, Д.В. Ефимова, А.А. Еремеев, Д.Э. Сабирова, С.Н. Гришин, А.У. ЗиганшинА.Е. Хайруллин, Д.В. Ефимова, А.А. Еремеев, Д.Э. Сабирова, С.Н. Гришин, А.У. Зиганшинhttps://journals.eco-vector.com/0869-8139/article/view/651565

It is known that in spinal motor neurons, after damage to the upper level of the spinal cord, neuronal degradation occurs, accompanied by axon degeneration. In the present study, the functional integrity of neuromuscular transmission was assessed by the method of stimulation mechanomiography. We demonstrated a decrease in the modulating activity of ATP in the cholinergic synapse due to spinal cord injury (a model of spinal cord contusion injury) in comparison with hypodynamia (a model of anti-orthostatic hanging of the hind limbs). The demonstrated abnormal modulation of the neuromuscular junction by purines provides evidence of axon degeneration and suggests that trans-synaptic degeneration of motor neurons may occur below the level of spinal cord injury in patients with similar injuries.

Известно, что в спинальных мотонейронах после поражения верхнего уровня спинного мозга происходит деградация нейронов, сопровождающаяся дегенерацией аксонов. В настоящем исследовании функциональная целостность нервно-мышечной передачи оценивалась методом стимуляционной механомиографии. Мы продемонстрировали снижение модулирующей активности АТФ в холинергическом синапсе вследствие травмы спинного мозга (модель контузионной травмы спинного мозга) в сравнении с гиподинамией (модель антиортостатического вывешивания задних конечностей). Продемонстрированная аномальная модуляция пуринами нервно-мышечного перехода предоставляет доказательства дегенерации аксонов и предполагает, что транссинаптическая дегенерация двигательных нейронов может происходить ниже уровня поражения спинного мозга у пациентов с подобными травмами.

denervationATPP2 receptorsskeletal muscleshypogravity motor syndrometraumatic motor syndromesynapsesuraminденервацияАТФР2-рецепторыскелетные мышцыгипогравитационный двигательный синдромтравматический двигательный синдромсинапссураминPollin MM, McHanwell S, Slater CR (1991) The effect of age on motor neurone death following axotomy in the mouse. Development 112(1): 83–89. https://doi.org/10.1242/dev.112.1.83Rishal I, Fainzilber M (2014) Axon-soma communication in neuronal injury. Nat Rev Neurosci 15(1): 32–42. https://doi.org/10.1038/nrn3609Jackson AB, Dijkers M, Devivo MJ, Poczatek RB (2004) A demographic profile of new traumatic spinal cord injuries: change and stability over 30 years. Arch Phys Med Rehabil 85(11): 1740–1748. https://doi.org/10.1016/j.apmr.2004.04.035Burns AS, Jawaid S, Zhong H, Yoshihara H, Bhagat S, Murray M, Roy RR, Tessler A, Son YJ (2007) Paralysis elicited by spinal cord injury evokes selective disassembly of neuromuscular synapses with and without terminal sprouting in ankle flexors of the adult rat. J Comp Neurol 500(1): 116–133. https://doi.org/10.1002/cne.21143Burns AS, Lemay MA, Tessler A (2005) Abnormal spontaneous potentials in distal muscles in animal models of spinal cord injury. Muscle Nerve 31(1): 46 –51. https://doi.org/10.1002/mus.20229Kaelan C, Jacobsen PF, Kakulas BA (1988) An investigation of possible transynaptic neuronal degeneration in human spinal cord injury. J Neurol Sci 86(2–3): 231–237. https://doi.org/10.1016/0022-510x(88)90101-3Bjugn R, Nyengaard JR, Rosland JH (1997) Spinal cord transection – no loss of distal ventral horn neurons. Modern stereological techniques reveal no transneuronal changes in the ventral horns of the mouse lumbar spinal cord after thoracic cord transection. Exp Neurol 148(1): 179 –186.Kirshblum S, Lim S, Garstang S, Millis S (2001) Electrodiagnostic changes of the lower limbs in subjects with chronic complete cervical spinal cord injury. Arch Phys Med Rehabil 82(5): 604–607. https://doi.org/10.1053/apmr.2001.22348Burns AS, Boyce VS, Tessler A, Lemay MA (2007) Fibrillation potentials following spinal cord injury: Improvement with neurotrophins and exercise. Muscle Nerve 35(5): 607–613. https://doi.org/10.1002/mus.20738Carter JG, Sokoll MD, Gergis SD (1981) Effect of spinal cord transection on neuromuscular function in the rat. Anesthesiology 55(5): 542–546. https://doi.org/10.1097/00000542-198111000-00011Dahlstrom A, Heiwall PO, Booj S, Dahllof AG (1978) The influence of supraspinal impulse activity on the intra-axonal transport of acetylcholine, choline acetyltransferase and acetylcholinesterase in rat motor neurons. Acta Physiol Scand 103(3): 308–319. https://doi.org/10.1111/j.1748-1716.1978.tb06218.xAkaaboune M, Culican SM, Turney SG, Lichtman JW (1999) Rapid and reversible effects of activity on acetylcholine receptor density at the neuromuscular junction in vivo. Science 286(5439): 503–507. https://doi.org/10.1126/science.286.5439.503Bruneau E, Sutter D, Hume RI, Akaaboune M (2005) Identification of nicotinic acetylcholine receptor recycling and its role in maintaining receptor density at the neuromuscular junction in vivo. J Neurosci 25(43): 9949–9959. https://doi.org/10.1523/JNEUROSCI.3169-05.2005Xiong GX, Zhang JW, Hong Y, Guan Y, Guan H (2008) Motor unit number estimation of the tibialis anterior muscle in spinal cord injury. Spinal Cord 46(10): 696–702. https://doi.org/10.1038/sc.2008.7Cotrina, ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M (1988) Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci U S A 95(26): 15735–15740. https://doi.org/10.1073/pnas.95.26.15735Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19(2): 520–528. https://doi.org/10.1523/JNEUROSCI.19-02-00520.1999Arcuino G, Lin JHC, Takano T, Liu C, Jiang L, Gao Q, Kang J, Nedergaard M (2002) Intercellular calcium signaling mediated by point-source burst release of ATP. Proc Natl Acad Sci U S A 99(15): 9840–9845. https://doi.org/10.1073/pnas.152588599Fields RD, Stevens-Graham B (2002) New insights into neuron-glia communication. Science 298(5593): 556–562. https://doi.org/10.1126/science.298.5593.556Haydon PG (2001) Glia: listening and talking to the synapse. Nat Rev Neurosci 2(3): 185–193. https://doi.org/10.1038/35058528Nedergaard M, Ransom B, Goldman S (2003) New roles for astrocytes: Redefining the functional architecture of the brain. Trends Neurosci 26(10): 523–530. https://doi.org/10.1016/j.tins.2003.08.008Fam SR, Gallagher CJ, Salter MW (2000) P2Y(1) purinoceptor-mediated Ca2+ signaling and Ca2+ wave propagation in dorsal spinal cord astrocytes. J Neurosci 20(8): 2800–2808. https://doi.org/10.1523/JNEUROSCI.20-08-02800.2000Khakh BS, North RA (2006) P2X receptors as cell-surface ATP sensors in health and disease. Nature 442(7102): 527–532. https://doi.org/10.1038/nature04886Gourine AV, Dale N, Llaudet E, Poputnikov DM, Spyer KM, Gourine VN (2007) Release of ATP in the central nervous system during systemic inflammation: Real-time measurement in the hypothalamus of conscious rabbits. J Physiol 585(Pt 1): 305–316. https://doi.org/10.1113/jphysiol.2007.143933Wang X, Arcuino G, Takano T, Lin J, Peng WG, Wan P, Li P, Xu Q, Liu QS, Goldman SA, Nedergaard M (2004) P2X7 receptor inhibition improves recovery after spinal cord injury. Nature Med 10(8): 821–827. https://doi.org/10.1038/nm1082North A (2002) Molecular physiology of P2X receptors. Physiol Rev 82(4): 1013–1067. https://doi.org/10.1152/physrev.00015.2002Solle M, Labasi J, Perregaux DG, Stam E, Petrushova N, Koller BH, Griffiths RJ, Gabel CA (2001) Altered cytokine production in mice lacking P2X7 receptors. J Biol Chem 276(1): 125–132. https://doi.org/10.1074/jbc.M006781200Kahlenberg J, Dubyak GW (2004) Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release. Am J Physiol 286(5): 1100–1108. https://doi.org/10.1152/ajpcell.00494.2003Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, Bonventre JV, Woolf CJ (2001) Interleukin-1beta-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature 410(6827): 471– 475. https://doi.org/10.1038/35068566Suzuki T, Hide I, Ido K, Kohsaka S, Inoue K, Nakata Y (2004) Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J Neurosci 24(1): 1–7. https://doi.org/10.1523/JNEUROSCI.13-12-05153.1993Allen AR (1911) Surgery of experimental lesion of spinal cord equivalent to crush injury of fracture dislocation of spinal column: a preliminary report. JAMA 57: 878–880.Ильин ЕА, Новиков ВЕ (1980) Стенд для моделирования физиологических эффектов невесомости в лабораторных экспериментах с крысами. Косм биол авиакосм мед 14(3): 79–80. [Ilyin EA, Novikov VE (1980) Stand for modeling the physiological effects of weightlessness in laboratory experiments with rats. Cosm biol aerocosm med 14(3): 79–80. (In Russ)].Morey-Holton ER, Globus RK (2002) Hindlimb unloading rodent model: technical aspects. J Appl Physiol 92(4): 1367–1377. https://doi.org/10.1152/japplphysiol.00969.2001Morey-Holton ER, Globus RK (1988) Hindlimb unloading of growing rats: a model for predicting skeletal changes during space flight. Bone 22(5 Suppl): 83–88. https://doi.org/10.1016/s8756-3282(98)00019-2Khairullin AE, Efimova DV, Markosyan VA, Grishin SN, Teplov AY, Ziganshin AU (2021) The effect of acute unilateral denervation injury on purinergic signaling in the cholinergic synapse. Biophysics 66(3): 483–486. https://doi.org/10.1134/S0006350921030064Profyris C, Cheema SS, Zang DW, Azari MF, Boyle K, Petratos S (2004) Degenerative and regenerative mechanisms governing spinal cord injury. Neurobiol Disease 15(3): 415–436. https://doi.org/10.1016/j.nbd.2003.11.015Beattie MS, Farooqui AA, Bresnahan JC (2000) Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma 17(10): 915 – 925. https://doi.org/10.1089/neu.2000.17.915Peng W, Cotrina ML, Han X, Yu H, Bekar L, Blum L, Takano T, Tian GF, Goldman SA, Nedergaard M (2009) Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. Proc Natl Acad Sci U S A 106(30): 12489–12493. https://doi.org/10.1073/pnas.0902531106Grafe P, Schaffer V, Rucker F (2006) Kinetics of ATP release following compression injury of a peripheral nerve trunk. Purinerg Signal 2: 527– 536.Cook SP, McCleskey EW (2002) Cell damage excites nociceptors through release of cytosolic ATP. Pain 95(1–2): 41–47.Neary JT, Kang Y, Willoughby KA, Ellis EF (2003) Activation of extracellular signal-regulated kinase by stretch-induced injury in astrocytes involves extracellular ATP and P2 purinergic receptors. J Neurosci 23(6): 2348–2356. https://doi.org/10.1523/JNEUROSCI.23-06-02348.2003Du S, Rubin A, Klepper S, Barrett C, Kim YC, Rhim HW, Lee EB, Park CW, Markelonis GJ, Oh TH (1999) Calcium influx and activation of calpain I mediate acute reactive gliosis in injured spinal cord. Exp Neurol 157(1): 96–105. https://doi.org/10.1006/exnr.1999.7041Stokes BT, Fox P, Hollinden G (1983) Extracellular calcium activity in the injured spinal cord. Exp Neurol 80(3): 561–572.Nilsson P, Hillered L, Olsson Y, Sheardown MJ, Hansen AJ (1993) Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats. J Cereb Blood Flow Metab 13(2): 183–192. https://doi.org/10.1038/jcbfm.1993.22Stout C, Charles A (2003) Modulation of intercellular calcium signaling in astrocytes by extracellular calcium and magnesium. Glia 43(3): 265–273. https://doi.org/10.1002/glia.10257Bianchi BR, Lynch KJ, Touma E, Niforatos W, Burgard EC, Alexander KM, Park HS, Yu H, Metzger R, Kowaluk E, Jarvis MF, Biesen T (1999) Pharmacological characterization of recombinant human and rat P2X receptor subtypes. Eur J Pharmacol 376(1–2): 127–138. https://doi.org/10.1002/glia.10257Di Virgilio, Chiozzi FP, Falzoni S, Ferrari D, Sanz JM, Venketaraman V, Baricordi OR (1998) Cytolytic P2X purinoceptors. Cell Death Differ 5(3): 191–199.Deuchars SA, Atkinson L, Brooke RE, Musa H, Milligan CJ, Batten TF, Buckley NJ, Parson SH, Deuchars J (2001) Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J Neurosci 21(18): 7143–7152. https://doi.org/10.1523/JNEUROSCI.21-18-07143.2001Gerasimenko YP, Avelev VD, Nikitin OA, Lavrov IA (2003) Initiation of locomotor activity in spinal cats by epidural stimulation of the spinal cord. Neurosci Behav Physiol 33(3): 247–254. https://doi.org/10.1023/a:1022199214515Lavrov I, Dy CJ, Fong AJ, Gerasimenko Y, Courtine G, Zhong H, Roy RR, Edgerton VR (2008) Epidural stimulation induced modulation of spinal locomotor networks in adult spinal rats. J Neurosci 28(23): 6022–6029. https://doi.org/10.1523/JNEUROSCI.0080-08.2008Irnich D, Burgstahler R, Bostock H, Grafe P (2001) ATP affects both axons and Schwann cells of unmyelinated C fibers. Pain 92: 343–350. https://doi.org/10.1016/S0304-3959(01)00277-9Lucas DR, Newhouse JP (1957) The Toxic Effect of Sodium L-Glutamate on the Inner Layers of the Retina. AMA Archiv Ophthalmol 58(2): 193–201. https://doi.org/10.1001/archopht.1957.00940010205006