Neuroprotective effects of testosterone on motoneuron and muscle morphology following spinal cord injury

Journal of Comparative Neurology

Volumn 520, Issue 12, 2012, Pages 2683-2696

  Byers, James S ^a   Huguenard, Anna L ^a   Kuruppu, Dulanji ^a   Liu, Nai Kui ^b   Xu, Xiao Ming ^b   Sengelaub, Dale R ^a  

^a INDIANA UNIVERSITY   (United States)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Dendrites; Morphology; Neuroprotection; Steroids

Indexed keywords

HORSERADISH PEROXIDASE; SILASTIC; TESTOSTERONE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL ASSAY; CELL COUNT; CELL VOLUME; CELLULAR DISTRIBUTION; CONTROLLED STUDY; DENDRITIC SPINE; DRUG EFFECT; FEMALE; GRAY MATTER; MORPHOMETRICS; MOTONEURON; MUSCLE CELL; MUSCLE FUNCTION; MUSCLE MASS; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; QUADRICEPS FEMORIS MUSCLE; RAT; SPINAL CORD INJURY; VASTUS LATERALIS MUSCLE; WHITE MATTER;

ANIMALS; DISEASE MODELS, ANIMAL; FEMALE; MOTOR NEURONS; MUSCLE, SKELETAL; MUSCULAR ATROPHY; NEUROPROTECTIVE AGENTS; RATS; RATS, SPRAGUE-DAWLEY; SPINAL CORD INJURIES; TESTOSTERONE;

EID: 84862130602     PISSN: 00219967     EISSN: 10969861     Source Type: Journal    
DOI: 10.1002/cne.23066     Document Type: Article

References (106)

1. Ahlbom E, Prins GS, Ceccatelli S. 2001. Testosterone protects cerebellar granule cells from oxidative stress-induced cell death through a receptor mediated mechanism. Brain Res 892: 255-262.
2. Al-Majed AA, Brushart TM, Gordon T. 2000. Electrical stimulation accelerates and increases expression of BDNF and trkB rnRNA in regenerating rat femoral motoneurons. Eur J Neurosci 12: 4381-4390.
3. Bamber NI, Huaying L, Xiaobin L, Oudenga M, Aebischer P, Xu XM. 2001. Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels. Eur J Neurosci 13: 257-268.
4. Bernstein JJ, Standler N. 1983. Dendritic alteration of rat spinal motoneurons after dorsal horn mince: computer reconstruction of dendritic fields. Exp Neurol 82: 532-540.
5. Bernstein JJ, Wacker W, Standler N. 1984. Spinal motoneuron dendritic alteration after spinal cord hemisection in the rat. Exp Neurol 83: 548-554.
6. Bialek M, Zaremba P, Borowicz KK, Czuczwar SJ. 2004. Neuroprotective role of testosterone in the nervous system. Pol J Pharmacol 56: 509-518.
7. Bisby MA, Tetzlaff W. 1992. Changes in cytoskeletal protein synthesis following axon injury and during regeneration. Mol Neurobiol 6: 107-123.
8. Brännström T, Havton L, Kellerth J-O. 1992. Changes in size and dendritic arborization patterns of adult cat spinal α-motoneurons following permanent axotomy. J Comp Neurol 318: 439-451.
9. Brösamle C, Schwab ME. 1997. Cells of origin, course, and termination patterns of the ventral, uncrossed component of the mature rat corticospinal tract. J Comp Neurol 386: 293-303.
10. Brown LT. 1971. Projections and termination of the corticospinal tract in rodents. Exp Brain Res 13: 432-450.
11. Brown LT. 1974. Rubrospinal projections in the rat. J Comp Neurol 154: 169-188.
12. II-tubulin mRNA in spinal motoneurons following sciatic nerve injury. Rest Neurol Neurosci 18: 191-198.
13. Brushart TM, Seiler WA. 1987. Selective reinnervation of distal motor stumps by peripheral axons. Exp Neurol 97: 290-300.
14. Castro-Moure F, Goshgarian HG. 1997. Morphological plasticity induced in the phrenic nucleus following cervical cold block of descending respiratory drive. Exp Neurol 147: 299-310.
15. Chaovipoch P, Jelks KA, Gerhold LM, West EJ, Chongthammakun S, Floyd CL. 2006. 17 Beta-estradiol is protective in spinal cord injury in post- and pre-menopausal rats. J Neurotrauma 23: 830-852.
16. Clark MJ, Petroski GF, Mazurek MO, Hagglund KJ, Sherman AK, Lammy AB, Childers MK, Acuff ME. 2008. Testosterone replacement therapy and motor function in men with spinal cord injury. Am J Phys Med Rehabil 87: 281-284.
17. Coers S, Tanzer L, Jones KJ. 2002. Testosterone treatment attenuates the effects of facial nerve transection on glial fibrillary acidic protein (GFAP) levels in the hamster facial motor nucleus. Metab Brain Dis 17: 55-63.
18. Coons KD, Muñoz F, Osborne MC, Sengelaub DR. 2009. Dendritic atrophy following partial motoneuron depletion: time course of recovery and protection with androgens and estrogens. In: Proceedings of the 39th Meeting of the Society for Neuroscience, Chicago, IL, 2009 (Abstract No. 743.2).
19. Diaz-Ruiz A, Ibarra A, Perez-Severiano F, Guizar-Sahagun G, Grijalva I, Rios C. 2002. Constituitive and inducible nitric oxide synthase activities after spinal cord contusion in rats. Neurosci Lett 319: 129-132.
20. Doherty JG, Burns AS, O'Ferrall DM, Ditunno JF, Jr. 2002. Prevalence of upper motor neuron vs. lower motor neuron lesions in complete lower thoracic and lumbar spinal cord injuries. J Spinal Cord Med 25: 289-292.
21. Fargo KN, Sengelaub DR. 2004a. Testosterone manipulation protects motoneurons from dendritic atrophy after contralateral motoneuron depletion. J Comp Neurol 469: 96-106.
22. Fargo KN, Sengelaub DR. 2004b. Exogenous testosterone prevents motoneuron atrophy induced by contralateral motoneuron depletion. J Neurobiol 60: 348-359.
23. Fargo KN, Sengelaub DR. 2007. Androgenic, but not estrogenic, protection of motoneurons from somal and dendritic atrophy induced by the death of neighboring motoneurons. Dev Neurobiol 67: 1094-1106.
24. Fargo KN, Alexander TD, Tanzer L, Poletti A, Jones KJ. 2008a. Androgen regulates neuritin mRNA in an in vivo model of steroid-enhanced peripheral nerve regeneration. J Neurotrauma 25: 561-566.
25. Fargo KN, Galbiati M, Foecking EM, Poletti A, Jones KJ. 2008b. Androgen regulation of axon growth and neurite extension in motoneurons. Horm Behav 53: 716-728.
26. Fargo NK, Foecking EM, Jones KJ, Sengelaub DR. 2009a. Neuroprotective actions of androgens on motoeneurons. Front Neuroendocrinol 30: 130-141.
27. Fargo KN, Foster AM, Sengelaub DR. 2009b. Neuroprotective effect of testosterone treatment on motoneuron recruitment following the death of nearby motoneurons. Dev Neurobiol 69: 825-835.
28. Farooque M, Suo Z, Arnol PM, Wulser MJ, Chou C-T, Vancura RW, Fowler S, Festoff BW. 2006. Gender-related differences in recovery of locomotor function after spinal cord injury in mice. Spinal Cord 44: 182-187.
29. Forgie ML, Kolb B. 2003. Manipulation of gonadal hormones in neonatal rats alters the morphological response of cortical neurons to brain injury in adulthood. Behav Neurosci 117: 257-262.
30. Gazula V-R, Roberts M, Luzzio C, Jawad AF, Kalb R. 2004. Effects of limb exercise after spinal cord injury on motor neuron dendrite structure. J Comp Neurol 476: 130-145.
31. Giangregorio L, McCartney N. 2006. Bone loss and muscle atrophy in spinal cord injury: epidemiology, fracture prediction, and rehabilitation strategies. J Spinal Cord Med 29: 489-500.
32. Goldstein LA, Sengelaub DR. 1994. Differential effects of dihydrotestosterone and estrogen on the development of motoneuron morphology in a sexually dimorphic rat spinal nucleus. J Neurobiol 25: 878-892.
33. Goldstein LA, Kurz EM, Sengelaub DR. 1990. Androgen regulation of dendritic growth and retraction in the development of a sexually dimorphic spinal nucleus. J Neurosci 10: 935-946.
34. Goldstein LA, Kurz EM, Kalkbrenner AE, Sengelaub DR. 1993. Changes in dendritic morphology of rat spinal motoneurons during development and after unilateral target deletion. Dev Brain Res 73: 151-163.
35. Goldspink DF. 1978. The influence of immobilization and stretch on protein turnover of rat skeletal muscle. J Physiol (Lond) 264: 267-282.
36. Gordan T, Mao J. 1994. Muscle atrophy and procedures for training after spinal cord injury. Phys Ther 74: 50-60.
37. Gundersen HJG. 1988. The nucleator. J Microsc 151: 3-21.
38. Hauben E, Mizrahi T, Agranov E, Schwartz M. 2002. Sexual dimorphism in the spontaneous recovery from spinal cord injury: a gender gap in beneficial autoimmunity? Eur J Neurosci 16: 1731-1740.
39. Hebbeler SL, Sengelaub DR. 2003. Development of a sexually dimorphic neuromuscular system in male rats after spinal transection: morphologic changes and implications for estrogen sites of action. J Comp Neurol 467: 80-96.
40. Hebbeler SL, Verhovshek T, Sengelaub DR. 2002. N-methyl-D-aspartate receptor blockade inhibits estrogenic support of dendritic growth in a sexually dimorphic rat spinal nucleus. J Comp Neurol 451: 142-152.
41. Hedreen JC, Bacon SJ, Price DL. 1985. A modified histochemical technique to visualize acetylcholinesterase-containing axons. J Histochem Cytochem 33: 134-40.
42. Henderson VW, Reynolds DW. 2002. Protective effects of estrogen on aging and damaged neural systems. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, editors. Hormones, brain and behavior. San Diego: Academic Press. p 821-837.
43. Hoang TX, Nieto J, Tillakaratne NJK, Havton LA. 2003. Autonomic and motor neuron death is progressive and parallel in a lumbosacral ventral root avulsion model of cauda equina injury. J Comp Neurol 467: 477-486.
44. Huguenard AL, Fernando SM, Monks DA, Sengelaub DR. 2011. Overexpression of androgen receptors in target musculature confers androgen sensitivity to motoneuron dendrites. Endocrinology 152: 639-650.
45. Iannotti C, Zhang YP, Shields CB, Han Y, Burke DA, Xu X-M. 2004. A neuroprotective role of glial cell line-derived neurotrophic factor following moderate spinal cord contusion injury. Exp neurol 189: 317-332.
46. Jones BE, Yang T-Z. 1985. The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J Comp Neurol 242: 56-92.
47. Jones KJ, Oblinger MM. 1994. Androgenic regulation of tubulin gene expression in axotomized hamster facial motoneurons. J Neurosci 14: 3620-3627.
48. Jones KJ, Durica TE, Jacob SK. 1997a. Gonadal steroid preservation of central synaptic input to hamster facial motoneurons following peripheral axotomy. J Neurocytol 26: 257-266.
49. Jones KJ, Kinderman NB, Oblinger MM. 1997b. Alterations in glial fibrillary acidic protein (GFAP) mRNA levels in the hamster facial motor nucleus: effects of axotomy and testosterone. Neurochem Res 22: 1359-1366.
50. Jones KJ, Coers S, Storer PD, Tanzer L, Kinderman NB. 1999a. Androgenic regulation of the central glia response following nerve damage. J Neurobiol 40: 560-573.
51. Jones KJ, Storer PD, Drengler SM, Oblinger, MM. 1999b. Differential regulation of cytoskeletal gene expression in hamster facial motoneurons: effects of axotomy and testosterone treatment. J Neurosci Res 57: 817-823.
52. Jones KJ, Brown TJ, Damaser M. 2001. Neuroprotective effects of gonadal steroids on regenerating peripheral motoneurons. Brain Res Rev 37: 372-382.
53. Kachadroka S, Hall AM, Niedzielko TL, Chongthammakun S, Floyd CL. 2010 Effect of endogenous androgens on 17 beta-estradiol-mediated protection after spinal cord injury in male rats. J. Neurotrauma 27: 611-626.
54. Kalb RG. 1994. Regulation of motor neuron dendrite growth by NMDA receptor activation. Development 120: 3063-3071.
55. Kinderman NB, Jones KJ. 1993. Testosterone enhancement of the nerve cell body response to injury: evidence using in situ hybridization and ribosomal DNA probes. J Neurosci 13: 1523-1532.
56. Kochakian CD. 1975. Definition of androgens and protein anabolic steroids. Pharmacol Ther B 1: 149-177.
57. Kujawa KA, Kinderman NB, Jones KJ. 1989. Testosterone-induced acceleration of recovery from facial paralysis following crush axotomy of the facial nerve in male hamsters. Exp Neurol 105: 80-85.
58. Kurz EM, Sengelaub DR, Arnold AP. 1986. Androgens regulate the dendritic length of mammalian motoneurons in adulthood. Science 232: 395-398.
59. Kurz EM, Brewer RG, Sengelaub DR. 1991. Hormonally mediated plasticity of motoneuron morphology in the adult rat spinal cord: a cholera toxin-HRP study. J Neurobiol 22: 976-988.
60. Leslie M, Forger NG, Breedlove SM. 1991. Does androgen affect axonal transport of cholera toxin HRP in spinal motoneurons? Neurosci Lett 126: 199-202.
61. Little, CM, Coons KD, Sengelaub DR. 2009. Neuroprotective effects of testosterone on the morphology and function of somatic motoneurons following the death of neighboring motoneurons. J Comp Neurol 512: 359-372.
62. Liu D, Thangnipon W, McAdoo DJ. 1991. Excitatory amino acids rise to toxic levels upon impact injury to the rat spinal cord. Brain Res 547: 344-348.
63. Liu NK, Xu XM. 2010. Phospholipase A2 and its molecular mechanism after spinal cord injury. Mol Neurobiol 41: 197-205.
64. Liu NK, Titsworth WL, Xu XM. 2009. Phospholipase A2 in CNS disorders: implication on traumatic spinal cord and brain injuries. In: Lajtha A, editor. Handbook of neurochemistry and molecular neurobiology. New York: Springer. p 321-341.
65. Liu XZ, Xu XM, Hu R, Du C, McDonald JW, Dong HX, Wu YJ, Fan GS, Jacquin MF, Hsu CY, Choi DW. 1997. Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 17: 5395-5406.
66. Loy DN, Talbott JF, Onifer SM, Mills MD, Burke DA, Dennison JB, Fajardo LC, Magnuson DSK, Whittemore SR. 2002. Both dorsal and ventral spinal cord pathways contribute to overground locomotion in the adult rat. Exp Neurol 177: 575-580.
67. Ma J, Novikov LN, Wiberg M, Kellerth J-O. 2001. Delayed loss of spinal motoneurons after peripheral nerve injury in adult rats: a quantitative morphological study. Exp Brain Res 139: 216-223.
68. Magnuson DSK, Trinder TC, Zhang YP, Burke D, Morassutti DJ, Shields CB. 1999. Comparing deficits following excitotoxic and contusion injuries in the thoracic and lumbar spinal cord of the adult rat. Exp Neurol 156: 191-204.
69. Marron TU, Guerini V, Rusmini P, Sau D, Brevini TA, Martini L, Poletti A. 2005. Androgen-induced neurite outgrowth is mediated by neuritin in motor neurons. J Neurochem 92: 10-20.
70. Martin GF, Vertes RP, Waltzer R. 1985. Spinal projections of the gigantocelluar reticular formation in the rat. Evidence for projections from different areas to laminae I and II and lamina IX. Exp Brain Res 58: 154-162.
71. Matsumoto A, Arai Y, Urano A, Hyodo S. 1994. Androgen regulates gene expression of cytoskeletal proteins in adult rat motoneurons. Horm Behav 28: 357-366.
72. Mesulam MM. 1982. Tracing neural connections with horseradish peroxidase. New York: John Wiley & Sons.
73. Menétey D, De Pommery J, Roudier F. 1985. Propriospinal fibers reaching the lumbar enlargement in the rat. Neurosci Lett 58: 257-261.
74. Michel RP, Cruz-Orive LM. 1988. Application of the Cavalieri principle and vertical sections method to lung: estimation of volume and pleural surface area. J Microsc 150: 117-136.
75. Moschilla G, Song S, Chakera T. 2001. Post-traumatic lumbar nerve root avulsion. Austral Radiol 45: 281-284.
76. Motorina MV. 1977. Distribution of reticulospinal fibers and their terminations in lumbar segments of the rat spinal cord. J Evol Biochem Physiol 12: 520-527.
77. National Center for Injury Prevention and Control. 2002. CDC injury fact book. Available at:
78. National Institute of Neurological Disorders and Stroke. 2005. Spinal cord injury: Emerging concepts. Available at:
79. Nicolopoulos-Stournaras S, Iles JF. 1983. Motor neuron columns in the lumbar spinal cord of the rat. J Comp Neurol 217: 75-85.
80. O'Hanlon GM, Lowrie MB. 1995. Nerve injury in adult rats causes abnormalities in the motoneuron dendritic field that differ from those seen following neonatal nerve injury. Exp Brain Res 103: 243-250.
81. Oorschot DE. 1994. Are you using neuronal densities, synaptic densities or neurochemical densities as your definitive data? There is a better way to go. Prog Neurobiol 44: 247-433.
82. Osborne MC, Verhovshek T, Sengelaub DR. 2007. Androgen regulates trkB expression in spinal motoneurons. J Neurosci Res 85, 303-309.
83. Pan Y, Zhang H, Acharya A, Patrick PH, Oliver D, Morley JE. 2004. Effect of testosterone on functional recovery in the castrate male rat stroke model. Presented at the Annual Meeting of the American Neurological Association, Toronto, October 3-6, 2004.
84. Peckham PH, Mortimer JT Marsolais EB. 1976. Alteration in the force and fatigability of skeletal muscle in quadriplegic humans following exercise induced by chronic electrical stimulation. Clin Orthop 114: 326-333.
85. Pike CJ. 2001. Testosterone attenuates β-amyloid toxicity in cultured hippocampal neurons. Brain Res 919: 160-165.
86. Pike CJ, Nguyen T-V V, Ramsden M, Yao M, Murphy MP, Rosario ER. 2008. Androgen cell signaling pathways involved in neuroprotective actions. Horm Behav 53: 693-705.
87. Raineteau O, Schwab ME. 2001. Plasticity of motor systems after incomplete spinal cord injury. Nat Rev Neurosci 2: 263-273.
88. Ritz M-F, Hausmann ON. 2008. Effect of 17B-estradiol on functional outcome, release of cytokines, astrocyte reactivity and inflammatory spreading after spinal cord injury in male rats. Brain Res 1203: 177-188.
89. Schwartz KR, Fee DB, Joy KM, Roberts KN, Sun S, Scheff NN, Wilson ME, Scheff SW. 2007. Gender differences in spinal cord injury are not estrogen-dependent. J Neurotrauma 24: 473-480.
90. Smith ER, Damassa DA, Davidson JM. 1977. Hormone administration: peripheral and intracranial implants. In: Meyer RD, editor. Methods in psychobiology. New York: Academic Press. p 259-279.
91. Srbnick EA, Wingrave JM, Matzelle DD, Wilford GG, Ray SK, Banik NL. 2005. Estrogen attenuated markers of inflammation and decreased lesion volume in acute spinal cord injury rats. J Neurosci Res 82: 283-293.
92. Standler N, Bernstein JJ. 1984. Dendritic alteration of spinal motoneurons after ablation of somatomotor cortex. Exp Neurol 83: 264-273.
93. Sumner BEH, Watson WE. 1971. Retraction and expansion of the dendritic tree of motor neurons of adult rats induced in vivo. Nature 233: 273-275.
94. Tetzlaff J, Tanzer L, Jones KJ. 2007. Exogenous androgen treatment delays the stress response following hamster facial nerve injury. J Neuroendocrinol 19: 383-389.
95. Titmus MJ, Faber DS. 1990. Axotomy-induced alterations in the electrophysiological characteristics of neurons. Prog Neurobiol 35: 1-51.
96. Verhovshek T, Cai Y, Osborne MC, Sengelaub DR. 2010. Androgen regulates brain-derived neurotrophic factor in spinal motoneurons and their target musculature. Endocrinology 151: 253-261.
97. Waldron HA, Gwyn DG. 1969. Descending nerve tracts in the spinal cord of the rat. I. Fibers from the midbrain. J Comp Neurol 137: 143-154.
98. Wang CX, Olshowka, JA, Wrathall JR. 1997. Increase of interleukin-1beta mRNA and protein in the spinal cord following experimental traumatic injury in the rat. Brain Res 759: 190-196.
99. Wilhelm JC, Cucoranu D, Gu J, Mulligan A, English AW. 2009. Limited peripheral axon regeneration in conditional BDNF knockout mice. In: Proceedings of the 39th Meeting of the Society for Neuroscience, Chicago, IL, 2009 (Abstract No. 510.8).
100. Williams PE, Goldspink G. 1973. The effect of immobilization on the longitudinal growth of striated muscle fibers. J Anat 116: 45-55.
101. Wilson RE, Coons KD, Sengelaub DR. 2009. Neuroprotective effects of testosterone on dendritic morphology following partial motoneuron depletion: efficacy in female rats. Neurosci Lett 465: 123-127.
102. Woolley CS, Cohen RS. 2002. Sex steroids and neuronal growth in adulthood. In: Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RT, editors. Hormones, brain and behavior. San Diego: Academic Press. p 717-777.
103. Xu XM, Zhang SX, Li H, Aebischer P, Bunge MB. 1999. Regrowth of axons into the distal spinal cord through Schwann cell-seeded mini-channels implanted into the hemisected adult spinal cord. Eur J Neurosci 11: 1723-1740.
104. Yang LY, Verhovshek T, Sengelaub DR. 2004. BDNF and androgen interact in the maintenance of dendritic morphology in a sexually dimorphic rat spinal nucleus. Endocrinology 145: 161-168.
105. Yune TY, Kim SJ, Lee SM, Lee YK, Oh YJ, Kim YC, Markelonis GJ, Oh TH. 2004. Systemic administration of 17 beta-estradiol reduces apoptotic cell death and improves functional recovery following traumatic spinal cord injury in rats. J Neurotrauma 21: 293-306.
106. Zhang Y, Champagne N, Beitel LK, Goodyer CG, Trifiro M, LeBlanc A. 2004. Estrogen and androgen protection of human neurons against intracellular amyloid beta1-42 toxicity through heat shock protein 70. J Neurosci 24: 5315-5321.