Abstract
Alterations in myelin membranes, as well as in the expression of myelin proteins have been reported in experimental models of diabetes. Data here reported show for the first time that the mRNA levels of two isoforms of myelin basic protein (MBP), 18.5 and 21.5 kDa, are decreased in the spinal cord of streptozotocin-treated rats and that treatment with a neuroactive steroid, such as progesterone (P), may counteract this effect. Interestingly, metabolism of progesterone into dihydroprogesterone (DHP) by the enzyme 5α-reductase seems to exert an important role in such an effect. As here demonstrated, 5α-reductase mRNA and DHP levels are reduced by diabetes in spinal cord, but treatment with P, is able to counteract these effects. Moreover, treatment with DHP is able to mimic the effect of P on MBP gene expression. Thus, the effects of P here observed are due to its enzymatic conversion into DHP. Because DHP, like P, interacts with P receptor (PR), the present results may suggest the importance to analyze the effects of PR modulators as tools of therapeutic strategies for diabetic complications occurring in nervous system.
References
Acs P, Kipp M, Norkute A et al (2009) 17beta-estradiol and progesterone prevent cuprizone provoked demyelination of corpus callosum in male mice. Glia 57:807–814
Azcoitia I, Leonelli E, Magnaghi V, Veiga S, Garcia-Segura LM, Melcangi RC (2003) Progesterone and its derivatives dihydroprogesterone and tetrahydroprogesterone reduce myelin fiber morphological abnormalities and myelin fiber loss in the sciatic nerve of aged rats. Neurobiol Aging 24:853–860
Belelli D, Lambert JJ (2005) Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat Rev Neurosci 6:565–575
Biessels GJ, Deary IJ, Ryan CM (2008) Cognition and diabetes: a lifespan perspective. Lancet Neurol 7:184–190
Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159
Ghoumari AM, Ibanez C, El-Etr M et al (2003) Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J Neurochem 86:848–859
Gispen WH, Biessels GJ (2000) Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 23:542–549
Hernandez-Fonseca JP, Rincon J, Pedreanez A et al (2009) Structural and ultrastructural analysis of cerebral cortex, cerebellum, and hypothalamus from diabetic rats. Exp Diabetes Res 2009:329632
Jacobson AM, Samson JA, Weinger K, Ryan CM (2002) Diabetes, the brain, and behavior: is there a biological mechanism underlying the association between diabetes and depression? Int Rev Neurobiol 51:455–479
Kawashima R, Kojima H, Nakamura K et al (2007) Alterations in mRNA expression of myelin proteins in the sciatic nerves and brains of streptozotocin-induced diabetic rats. Neurochem Res 32:1002–1010
Kodl CT, Seaquist ER (2008) Cognitive dysfunction and diabetes mellitus. Endocr Rev 29:494–511
Labombarda F, Gonzalez S, Gonzalez Deniselle MC et al (2006) Progesterone increases the expression of myelin basic protein and the number of cells showing NG2 immunostaining in the lesioned spinal cord. J Neurotrauma 23:181–192
Labombarda F, Gonzalez SL, Lima A et al (2009) Effects of progesterone on oligodendrocyte progenitors, oligodendrocyte transcription factors, and myelin proteins following spinal cord injury. Glia 57:884–897
Leonelli E, Bianchi R, Cavaletti G et al (2007) Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis. Neuroscience 144:1293–1304
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408
McCall AL (2002) Diabetes mellitus and the central nervous system. Int Rev Neurobiol 51:415–453
Melcangi RC, Magnaghi V, Cavarretta I et al (1999) Progesterone derivatives are able to influence peripheral myelin protein 22 and P0 gene expression: possible mechanisms of action. J Neurosci Res 56:349–357
Melcangi RC, Magnaghi V, Martini L (2000) Aging in peripheral nerves: regulation of myelin protein genes by steroid hormones. Prog Neurobiol 60:291–308
Melcangi RC, Garcia-Segura LM, Mensah-Nyagan AG (2008) Neuroactive steroids: state of the art and new perspectives. Cell Mol Life Sci 65:777–797
Pesaresi M, Maschi O, Giatti S, Garcia-Segura LM, Caruso D, Melcangi RC (2010) Sex differences in neuroactive steroid levels in the nervous system of diabetic and non-diabetic rats. Horm Behav 57:46–55
Roglio I, Bianchi R, Gotti S et al (2008a) Neuroprotective effects of dihydroprogesterone and progesterone in an experimental model of nerve crush injury. Neuroscience 155:673–685
Roglio I, Giatti S, Pesaresi M et al (2008b) Neuroactive steroids and peripheral neuropathy. Brain Res Rev 57:460–469
Roglio I, Bianchi R, Camozzi F et al (2009) Docetaxel-induced peripheral neuropathy: protective effects of dihydroprogesterone and progesterone in an experimental model. J Peripher Nerv Syst 14:36–44
Sasaki H, Schmelzer JD, Zollman PJ, Low PA (1997) Neuropathology and blood flow of nerve, spinal roots and dorsal root ganglia in longstanding diabetic rats. Acta Neuropathol 93:118–128
Schumacher M, Guennoun R, Ghoumari A et al (2007) Novel perspectives for progesterone in hormone replacement therapy, with special reference to the nervous system. Endocr Rev 28:387–439
Sugimoto K, Murakawa Y, Sima AA (2000) Diabetic neuropathy—a continuing enigma. Diabetes Metab Res Rev 16:408–433
Veiga S, Leonelli E, Beelke M, Garcia-Segura LM, Melcangi RC (2006) Neuroactive steroids prevent peripheral myelin alterations induced by diabetes. Neurosci Lett 402:150–153
Vinik AI, Park TS, Stansberry KB, Pittenger GL (2000) Diabetic neuropathies. Diabetologia 43:957–973
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The financial support of PRIN (20074SPYCM_002) and PUR from University of Milano, Italy, to Roberto C. Melcangi is gratefully acknowledged.
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Pesaresi, M., Giatti, S., Calabrese, D. et al. Dihydroprogesterone Increases the Gene Expression of Myelin Basic Protein in Spinal Cord of Diabetic Rats. J Mol Neurosci 42, 135–139 (2010). https://doi.org/10.1007/s12031-010-9344-y
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DOI: https://doi.org/10.1007/s12031-010-9344-y