Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: A multimodal analysis

E. Leonelli, R. Bianchi, G. Cavaletti, D. Caruso, D. Crippa, L. M. Garcia-Segura, G. Lauria, V. Magnaghi, I. Roglio, R. C. Melcangi

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Abstract

One important complication of diabetes is damage to the peripheral nervous system. However, in spite of the number of studies on human and experimental diabetic neuropathy, the current therapeutic arsenal is meagre. Consequently, the search for substances to protect the nervous system from the degenerative effects of diabetes has high priority in biomedical research. Neuroactive steroids might be interesting since they have been recently identified as promising neuroprotective agents in several models of neurodegeneration. We have assessed whether chronic treatment with progesterone (P), dihydroprogesterone (DHP) or tetrahydroprogesterone (THP) had neuroprotective effects against streptozotocin (STZ)-induced diabetic neuropathy at the neurophysiological, functional, biochemical and neuropathological levels. Using gas chromatography coupled to mass-spectrometry, we found that three months of diabetes markedly lowered P plasma levels in male rats, and chronic treatment with P restored them, with protective effects on peripheral nerves. In the model of STZ-induced of diabetic neuropathy, chronic treatment for 1 month with P, or with its derivatives, DHP and THP, counteracted the impairment of nerve conduction velocity (NCV) and thermal threshold, restored skin innervation density, and improved Na+,K+-ATPase activity and mRNA levels of myelin proteins, such as glycoprotein zero and peripheral myelin protein 22, suggesting that these neuroactive steroids, might be useful protective agents in diabetic neuropathy. Interestingly, different receptors seem to be involved in these effects. Thus, while the expression of myelin proteins and Na+,K+-ATPase activity are only stimulated by P and DHP (i.e. two neuroactive steroids interacting with P receptor, PR), NCV, thermal nociceptive threshold and intra-epidermal nerve fiber (IENF) density are also affected by THP, which interacts with GABA-A receptor. Because, a therapeutic approach with specific synthetic receptor ligands could avoid the typical side effects of steroids, future experiments will be devoted to evaluating the role of PR and GABA-A receptor in these protective effects.

Original languageEnglish
Pages (from-to)1293-1304
Number of pages12
JournalNeuroscience
Volume144
Issue number4
DOIs
Publication statusPublished - Feb 23 2007

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Diabetic Neuropathies
20-alpha-Dihydroprogesterone
Neuroprotective Agents
Progesterone
Steroids
Myelin Proteins
Neural Conduction
GABA-A Receptors
Streptozocin
Hot Temperature
Myelin P0 Protein
Artificial Receptors
Protective Agents
Peripheral Nervous System
Diabetes Complications
Peripheral Nerves
Nerve Fibers
Gas Chromatography
Nervous System
Biomedical Research

Keywords

  • diabetes
  • myelin
  • neuroactive steroids
  • rat
  • sciatic nerve
  • streptozotocin

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Leonelli, E., Bianchi, R., Cavaletti, G., Caruso, D., Crippa, D., Garcia-Segura, L. M., ... Melcangi, R. C. (2007). Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: A multimodal analysis. Neuroscience, 144(4), 1293-1304. https://doi.org/10.1016/j.neuroscience.2006.11.014

Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy : A multimodal analysis. / Leonelli, E.; Bianchi, R.; Cavaletti, G.; Caruso, D.; Crippa, D.; Garcia-Segura, L. M.; Lauria, G.; Magnaghi, V.; Roglio, I.; Melcangi, R. C.

In: Neuroscience, Vol. 144, No. 4, 23.02.2007, p. 1293-1304.

Research output: Contribution to journalArticle

Leonelli, E, Bianchi, R, Cavaletti, G, Caruso, D, Crippa, D, Garcia-Segura, LM, Lauria, G, Magnaghi, V, Roglio, I & Melcangi, RC 2007, 'Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: A multimodal analysis', Neuroscience, vol. 144, no. 4, pp. 1293-1304. https://doi.org/10.1016/j.neuroscience.2006.11.014
Leonelli, E. ; Bianchi, R. ; Cavaletti, G. ; Caruso, D. ; Crippa, D. ; Garcia-Segura, L. M. ; Lauria, G. ; Magnaghi, V. ; Roglio, I. ; Melcangi, R. C. / Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy : A multimodal analysis. In: Neuroscience. 2007 ; Vol. 144, No. 4. pp. 1293-1304.
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