Mitochondrial dysfunction in diabetic neuropathy may be involved in the development of neuropathic pain via a reduction in neurosteroid synthesis
Recent work in a model of diabetic neuropathy revealed that layer Background: 2/3 cortical pyramidal neurones of the pain pathway exhibited reduced endogenous neurosteroid modulation of the GABA R and exogenously applied neurosteroids had an exaggerated impact. It is postulated that this is related to reduced precursor synthesis, due to mitochondrial dysfunction in diabetic neuropathy. Benzodiazepines are also known to activate neurosteroidogenesis by binding to mitochondrial translocator
... translocator protein (TSPO). This study explored the differential effect of diazepam on GABA R modulation via neurosteroidogenesis in diabetic and wild type (WT) mice. Whole-cell patch-clamp technique was used on slices of neural Methods: tissue. Electrophysiological recordings were obtained from layer 2/3 cortical pyramidal neurons of the pain pathway from mice with type-II diabetic neuropathy ( ) and WT controls aged 60-80 days. ob/ob There was a key difference in the response of the WT and Results: ob/ob cortical neurons to simultaneous incubation with diazepam and flumazenil. In contrast, diazepam and the 5a-reductase inhibitor finasteride, individually or in combination, produced the same response in both strains. The exaggerated effect of diazepam on GABAergic inhibitory Conclusions: tone in the , despite the presence of the GABA R benzodiazepine ob/ob antagonist flumazenil is likely observed due to physiological upregulation of key neurosteroidogenic enzymes in response to the reduced pregnenolone synthesis by the mitochondria. By increasing pregnenolone via TSPO activation, it is possible to promote enhanced neurosteroidogenesis and increase GABAergic inhibitory tone via an alternate route. In diabetic neuropathic pain, mitochondrial dysfunction may play an important role. Enhancing the GABAergic neurosteroid tone could be of potential therapeutic benefit. No competing interests were disclosed. Competing interests: Humble SR. How to cite this article: Mitochondrial dysfunction in diabetic neuropathy may be involved in the development of neuropathic pain via a reduction in neurosteroid synthesis [version 1; referees: 1 approved, 1 approved with reservations] 2017, :506 (doi: ) References D'Hulst C, Atack JR, Kooy RF: The complexity of the GABA A receptor shapes unique pharmacological profiles. Drug Discov Today. 2009; 14(17-18): 866-875. PubMed Abstract | Publisher Full Text D'Mello R, Dickenson AH: Spinal cord mechanisms of pain. Br J Anaesth. 2008; 101(1): 8-16. PubMed Abstract | Publisher Full Text Do Rego JL, Seong JY, Burel D, et al.: Neurosteroid biosynthesis: enzymatic pathways and neuroendocrine regulation by neurotransmitters and neuropeptides. Front Neuroendocrinol. 2009; 30(3): 259-301. PubMed Abstract | Publisher Full Text Gatliff J, Campanella M: TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria. Biochem J. 2016; 473(2): 107-21. PubMed Abstract | Publisher Full Text Giatti S, Pesaresi M, Cavaletti G, et al.: Neuroprotective effects of a ligand of translocator protein-18 kDa (Ro5-4864) in experimental diabetic neuropathy. Neuroscience. 2009; 164(2): 520-529. PubMed Abstract | Publisher Full Text Harvey VL, Dickenson AH: Mechanisms of pain in nonmalignant disease. Curr Opin Support Palliat Care. 2008; 2(2): 133-139. PubMed Abstract | Publisher Full Text Hosie AM, Wilkins ME, da Silva HM, et al.: Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature. 2006; 444(7118): 486-489. PubMed Abstract | Publisher Full Text Humble S: Dataset of 'Neurosteroids Are Reduced in Diabetic Neuropathy and May Be Associated with the Development of Neuropathic Pain'. Open Science Framework. 2016b. Publisher Full Text Humble SR: Neurosteroids; endogenous analgesics? PhD Thesis, University of Dundee. 2013. Reference Source Humble SR: Neurosteroids are reduced in diabetic neuropathy and may be associated with the development of neuropathic pain [version 1; referees: 1 approved, 2 approved with reservations]. F1000Res. 2016a; 5: 1923. PubMed Abstract | Publisher Full Text | Free Full Text Papadopoulos V, Lecanu L: Translocator protein (18 kDa) TSPO: an emerging therapeutic target in neurotrauma. Exp Neurol. 2009; 219(1): 53-57. PubMed Abstract | Publisher Full Text | Free Full Text Rupprecht R, Papadopoulos V, Rammes G, et al.: Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010; 9(12): 971-988. PubMed Abstract | Publisher Full Text Schumacher M, Hussain R, Gago N, et al.: Progesterone synthesis in the nervous system: implications for myelination and myelin repair. Front Neurosci. 2012; 6: 10. PubMed Abstract | Publisher Full Text | Free Full Text Stocco DM, Zhao AH, Tu LN, et al.: A brief history of the search for the Protein(s) involved in the acute regulation of steroidogenesis. Mol Cell Endocrinol. 2017; 441: 7-16. PubMed Abstract | Publisher Full Text Tokuda K, O'Dell KA, Izumi Y, et al.: Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis. J Neurosci. 2010; 30(50): 16788-95. PubMed Abstract | Publisher Full Text | Free Full Text Zhang LM, Qiu ZK, Chen XF, et al.: Involvement of allopregnanolone in the anti-PTSD-like effects of AC-5216. J Psychopharmacol. 2016; 30(5): 474-81. PubMed Abstract | Publisher Full Text Supplementary material Supplementary Tables 1 and 2: Analysed raw data. Click here to access the data.