Cellular NeuroscienceResearch PaperNeuroprotective effects of a ligand of translocator protein-18kDa (Ro5-4864) in experimental diabetic neuropathy
Section snippets
Materials
5-pregnen-3β-ol-20-one (pregnenolone; PREG), PROG, 5α-pregnane-3, 20-dione (dihydroprogesterone; DHP), 3α-hydroxy-5α-pregnen-20-one (THP), 3β-hydroxy-5α-pregnen-20-one (isopregnanolone), T, 5α-androstane-17β-ol-3-one (dihydrotestosterone; DHT), 3α-diol, were purchased from Sigma Aldrich. 17,21,21,21-D4-PREG (D4-PREG) was kindly synthesized by Dr. P. Ferraboschi (Department of Medical Chemistry, Biochemistry and Biotechnology, University of Milano, Milano, Italy); 2,2,4,6,6–17α,21,21,21-D9-PROG
Results
We have here tested an experimental protocol of treatment previously utilized in case of neuroactive steroids and demonstrated to be protective in STZ rat (Leonelli et al 2007, Roglio et al 2007). Thus, animals received 16 treatments of Ro5-4864 and injections were administered every 2 days (experimental protocol 1). We have compared the effect of this experimental protocol with another one in which we have decreased the frequency of treatment. Thus, animals were injected once a week and
Discussion
Our recent results suggested that neuroactive steroids, such as PROG, T and their derivatives, might be considered as promising therapeutic strategy for diabetic neuropathy. The results of the present work demonstrate for the first time that stimulating TSPO with its ligand Ro5-4864 an increase of PREG (i.e. the first steroid synthesized from cholesterol) associated to an increase of its first derivative, PROG, and of a T metabolite, such as DHT, occurred directly in the sciatic nerve of STZ
Conclusion
Our findings indicate that Ro5-4864, a ligand of TSPO, is able to increase the low levels of neuroactive steroids, such as PREG, PROG and DHT, present in the sciatic nerve of STZ-induced diabetic neuropathy. Ro5-4864 also exerts neuroprotective actions against the pathological changes induced by experimental diabetes in peripheral nerves. These neuroprotective effects are most likely mediated by PREG, PROG, T and DHT, rather than by other neuroactive steroids, such as DHP, previously shown to
Acknowledgments
The financial support of PRIN (20074SPYCM_002) and PUR from Università degli Studi di Milano, Italy, to Roberto C. Melcangi is gratefully acknowledged.
References (61)
- et al.
Regulation of renal peripheral benzodiazepine receptors by anion transport inhibitors
Life Sci
(1988) - et al.
Characterization of peripheral type benzodiazepine binding sites in human and rat platelets by using [3H]PK 11195Studies in hypertensive patients
Biochem Pharmacol
(1984) - et al.
The metabolic clearance rate, head and brain extractions, and brain distribution and metabolism of progesterone in the anesthetized, female monkey (Macaca mulatta)
Brain Res
(1975) - et al.
Role of the peripheral-type benzodiazepine receptor in adrenal and brain steroidogenesis
Int Rev Neurobiol
(2001) - et al.
Evaluation of neuroactive steroid levels by liquid chromatography-tandem mass spectrometry in central and peripheral nervous system: effect of diabetes
Neurochem Int
(2008) - et al.
Peripheral benzodiazepine receptors and mitochondrial function
Neurochem Int
(2002) - et al.
Hypothalamic-pituitary-adrenal activity in type 2 diabetes mellitus: role of autonomic imbalance
Metabolism
(2006) - et al.
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction
Anal Biochem
(1987) - et al.
Diabetic neuropathy: mechanisms to management
Pharmacol Ther
(2008) - et al.
PK11195, a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection
Exp Cell Res
(1998)
Peripheral-type benzodiazepine receptor: structure and function of a cholesterol-binding protein in steroid and bile acid biosynthesis
Steroids
Enhanced expression of the peripheral benzodiazepine receptor (PBR) and its endogenous ligand octadecaneuropeptide (ODN) in the regenerating adult rat sciatic nerve
Neurosci Lett
Regulation of the expression of peripheral benzodiazepine receptors and their endogenous ligands during rat sciatic nerve degeneration and regeneration: a role for PBR in neurosteroidogenesis
Brain Res
Mitochondria in DRG neurons undergo hyperglycemic mediated injury through Bim, Bax and the fission protein Drp1
Neurobiol Dis
Progesterone and its derivatives are neuroprotective agents in experimental diabetic neuropathy: a multimodal analysis
Neuroscience
Ro5-4864, a synthetic ligand of peripheral benzodiazepine receptor, reduces aging-associated myelin degeneration in the sciatic nerve of male rats
Mech Ageing Dev
Protein measurement with the Folin phenol reagent
J Biol Chem
Role of the peripheral benzodiazepine receptor in sensory neuron regeneration
Mol Cell Neurosci
Brain mitochondrial dysfunction as a link between Alzheimer's disease and diabetes
J Neurol Sci
Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis
Steroids
Targeted disruption of the peripheral-type benzodiazepine receptor gene inhibits steroidogenesis in the R2C Leydig tumor cell line
J Biol Chem
Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders
Neuroscience
Neuroactive steroids and peripheral neuropathy
Brain Res Rev
Oxidative injury and neuropathy in diabetes and impaired glucose tolerance
Neurobiol Dis
Progesterone: therapeutic opportunities for neuroprotection and myelin repair
Pharmacol Ther
Neuroactive steroids prevent peripheral myelin alterations induced by diabetes
Neurosci Lett
The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging
Prog Neurobiol
Peripheral-type benzodiazepine receptor ligands and serum steroid hormones
Brain Res
Benzodiazepines, anxiety and immunity
Pharmacol Ther
Interaction of benzodiazepines with mouse macrophages
Eur J Pharmacol
Cited by (80)
A novel dual mode-of-action anti-hyperalgesic compound in rats which is neuroprotective and promotes neuroregeneration
2022, European Journal of PharmacologyNeurosteroids and neuropathic pain: An up-to-date perspective
2022, Current Opinion in Endocrine and Metabolic ResearchEndozepines and their receptors: Structure, functions and pathophysiological significance
2020, Pharmacology and TherapeuticsSex differences in steroid levels and steroidogenesis in the nervous system: Physiopathological role
2020, Frontiers in NeuroendocrinologyDevelopment of new treatments for Alzheimer's disease based on the modulation of translocator protein (TSPO)
2019, Ageing Research Reviews