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

Leonelli, Emanuela; Bianchi, Roberto; Cavaletti, Guido; Caruso, Donatella; Crippa, Donatella; García‐Segura, Luis M.; Lauria, Giuseppe; Magnaghi, Valerio; Roglio, Ilaria; Melcangi, Roberto Cosimo

doi:10.1016/j.neuroscience.2006.11.014

Cited by 173 publications

(151 citation statements)

References 69 publications

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“…2), indicates that there is a significant decrease in both IENFD as compared to non-diabetic controls. These data results for IENFD in controls and diabetics are similar to previously published reports in rats and humans (Bianchi et al, 2004;Hirai et al, 2000;Leonelli et al, 2007).…”

Section: Animal Characteristics and Quantitative Measurementssupporting

confidence: 92%

“…The timing of increases in TGF-β mRNA and protein show an association with decreased nerve conduction velocities, paw withdrawal threshold, IENFD and fiber length in the STZ diabetic model. IENFD is a good marker of early neuropathy both in rodents and humans (Bianchi et al, 2004;Hirai et al, 2000;Leonelli et al, 2007;Polydefkis et al, 2004). Other models of nerve injury, for example sciatic cryoneurolysis and chronic constriction injury, show a similar increase in cytokine production including TGF-β in the spinal cord and dorsal and ventral roots Willenbring et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

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Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Anjaneyulu

Berent-Spillson

Inoue

et al. 2008

Experimental Neurology

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The mechanism/s leading to diabetic neuropathy are complex. Transforming growth factor-β1 (TGF-β1) has been associated with diabetic nephropathy and retinopathy but not neuropathy. In this study, changes in TGF-β isoforms were examined in-vivo and in-vitro. Two groups of animals, streptozotocin diabetic with neuropathy and non-diabetic controls were examined at 4 weeks (n=10/ group) and 12 weeks (n=8/group). In diabetic DRG using quantitative real-time PCR (QRT-PCR), TGF-β1 and TGF-β2 mRNA, but not TGF-β3, was increased at 4 and 12 weeks. In sciatic nerve TGF-β3 mRNA was primarily increased. Immunohistochemistry (DRG) and immunoblotting (sciatic nerve) showed similar differential protein expression. In sciatic nerve TGF-β formed homoand heterodimers, of which β 2 /β 3 , β 1 /β 1 , and β 1 /β 3 were significantly increased, while that of the TGF-β 2 /β 2 homodimer was decreased, in diabetic compared to non-diabetic rats. In-vitro, pretreatment of embryonic DRG with TGF-β neutralizing antibody prevents the increase in total TGF-β protein observed with high glucose using immunoblotting. In high glucose conditions, combination with TGF-β2 > β1 increases the percent of cleaved caspase-3 compared to high glucose alone and TGF-β neutralizing antibody inhibits this increase. Furthermore, consistent with the findings in diabetic DRG and nerve, TGF-β isoforms applied directly in vitro reduce neurite outgrowth, and this effect is partially reversed by TGF-β neutralizing antibody. These findings implicate upregulation of TGF-β in experimental diabetic peripheral neuropathy and indicate a novel mechanism of cellular injury related to elevated glucose levels. In combination, these findings indicate a potential new target for treatment of diabetic peripheral neuropathy.

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Section: Animal Characteristics and Quantitative Measurementssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Anjaneyulu

Berent-Spillson

Inoue

et al. 2008

Experimental Neurology

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“…Some of these effects may be due to trophic actions and/or morphological factors associated with hormonal milieu. 3a,5a-THP is one such steroidogenic factor that is enhanced throughout pregnancy and has demonstrated neuroprotective and neuroproliferative effects , Djebaili et al 2005, Wang et al 2005, VanLandingham et al 2006, Leonelli et al 2007, Wang et al 2008. Of note, parity has been associated with reductions in age-related cognitive decrement and markers of neurodegeneration, as well as the increased expression of brain-derived neurotrophic factor (Gatewood et al 2005, Pawluski & Galea 2007, Macbeth et al 2008.…”

Section: Introductionmentioning

confidence: 99%

Estrous cycle, pregnancy, and parity enhance performance of rats in object recognition or object placement tasks

Paris¹,

Frye²

2008

Reproduction

113

104

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Ovarian hormone elevations are associated with enhanced learning/memory. During behavioral estrus or pregnancy, progestins, such as progesterone (P 4 ) and its metabolite 5a-pregnan-3a-ol-20-one (3a,5a-THP), are elevated due, in part, to corpora luteal and placental secretion. During 'pseudopregnancy', the induction of corpora luteal functioning results in a hormonal milieu analogous to pregnancy, which ceases after about 12 days, due to the lack of placental formation. Multiparity is also associated with enhanced learning/memory, perhaps due to prior steroid exposure during pregnancy. Given evidence that progestins and/or parity may influence cognition, we investigated how natural alterations in the progestin milieu influence cognitive performance. In Experiment 1, virgin rats (nulliparous) or rats with two prior pregnancies (multiparous) were assessed on the object placement and recognition tasks, when in high-estrogen/P 4 (behavioral estrus) or low-estrogen/P 4 (diestrus) phases of the estrous cycle. In Experiment 2, primiparous or multiparous rats were tested in the object placement and recognition tasks when not pregnant, pseudopregnant, or pregnant (between gestational days (GDs) 6 and 12). In Experiment 3, pregnant primiparous or multiparous rats were assessed daily in the object placement or recognition tasks. Females in natural states associated with higher endogenous progestins (behavioral estrus, pregnancy, multiparity) outperformed rats in low progestin states (diestrus, non-pregnancy, nulliparity) on the object placement and recognition tasks. In earlier pregnancy, multiparous, compared with primiparous, rats had a lower corticosterone, but higher estrogen levels, concomitant with better object placement performance. From GD 13 until post partum, primiparous rats had higher 3a,5a-THP levels and improved object placement performance compared with multiparous rats.

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“…Decreased NCV, together with reductions in Na + , K + -ATPase activity, is the hallmark of diabetic neuropathy, but these rats present various types of early neurological dysfunction [14], including altered pain sensation suggesting early involvement of small nociceptive sensory neurons [15]. Alterations in nociceptive threshold can be partially prevented and restored by erythropoietin, prosaposin-derived peptide and neuroactive steroids [14,16,17]. Hyperglycaemia plays a major role in the onset and progression of long-term diabetic complications, although insulin deficiency itself may also contribute [18].…”

Section: Introductionmentioning

confidence: 99%

Regression of diabetic complications by islet transplantation in the rat

et al. 2009

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Aims/hypothesis Type 1 diabetes is a chronic disease leading to complications such as peripheral neuropathies, nephropathy and cardiovascular disease. Pancreatic islet transplantation is being extensively investigated for blood glucose control in animals and in human type 1 diabetic patients, but the question of whether it can reverse long-term diabetic complications has not been fully explored. We investigated the effects of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes.Methods Three groups of rats were used: healthy controls, diabetic and diabetic rats transplanted with microencapsulated islets at 2 months after diabetes induction, when neuropathy was detectable by a decrease in tail nerve conduction velocity (NCV) and impaired nociceptive thresholds. Blood glucose levels and body weight were measured weekly. The variables considered were: thermal (hot plate test) and mechanical sensitivity (Randal-Selitto paw withdrawal test), NCV and Na+, K+-ATPase activity in the sciatic nerve. At the end of the experiments hearts were removed for morphometric determination and myocyte number, and kidneys removed for histological examination. Results Islet transplantation in diabetic rats induced normoglycaemia in a few days, accompanied by a rapid rise in body weight and amelioration of impaired nociceptive thresholds, as well as normalisation of NCV and Na + , K + -ATPase, which were both about 25% below normal in diabetic rats. Myocyte loss was reduced (−34%) by islet transplantation and the observed mild kidney damage of diabetic rats was prevented. Conclusions/interpretation Besides controlling glycaemia, transplantation of microencapsulated pancreatic islets induced almost complete regression of neuropathy and prevented cardiovascular alterations.

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

Cited by 173 publications

References 69 publications

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

Estrous cycle, pregnancy, and parity enhance performance of rats in object recognition or object placement tasks

Regression of diabetic complications by islet transplantation in the rat

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