Progesterone: Therapeutic opportunities for neuroprotection and myelin repair

Schumacher, Michaël; Guennoun, Rachida; Stein, Donald G.; Nicola, Alejandro F. De

doi:10.1016/j.pharmthera.2007.06.001

Cited by 217 publications

(161 citation statements)

References 443 publications

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“…The observed effects of progesterone on inflammation reduction, swelling, and apoptosis have been proposed to be caused by regulation of gene transcription, the modulation of neurotransmitter receptors, and the activation of signaling cascades (Schumacher et al, 2007). Progesterone has been shown previously to modulate the activity of neurotransmitters, including positive modulation of c-aminobutyric acid type A (GABA A ) receptors, primarily by allopregnanolone, the active metabolite of progesterone (Belelli et al, 2002;Majewska et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

Anderson

Farin

Bammler

et al. 2011

Journal of Neurotrauma

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Microarray-based transcriptional profiling was used to determine the effect of progesterone in the cortical contusion (CCI) model. Gene ontology (GO) analysis then evaluated the effect of dose on relevant biological pathways. Treatment (vehicle, progesterone 10 mg/kg or 20 mg/kg given i.p.) was started 4 h post-injury and administered every 12 h post-injury for up to 72 h, with the last injection 12 hr prior to death for the 24 h and 72 h groups. In the CCI-injured vehicle group compared to non-injured animals, expression of 1,114, 4,229, and 291 distinct genes changed > 1.5-fold ( p < 0.05) at 24 h, 72 h, and 7 days, respectively. At 24 h, the effect of low-dose progesterone on differentially expressed genes was < 20% the effect of higher dose compared to vehicle. GO analysis identified a significant effect of low-and high-dose progesterone treatment compared to vehicle on DNA damage response. At 72 h, high-dose progesterone treatment compared to vehicle affected expression of almost twice as many genes as did low-dose progesterone. Both low-and high-dose progesterone resulted in expression of genes regulating inflammatory response and apoptosis. At 7 days, there was only a modest difference in high-dose progesterone compared to vehicle, with only 14 differentially expressed genes. In contrast, low-dose progesterone resulted in 551 differentially expressed genes compared to vehicle. GO analysis identified genes for the low-dose treatment involved in positive regulation of cell proliferation, innate immune response, positive regulation of anti-apoptosis, and blood vessel remodeling.

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Section: Discussionmentioning

confidence: 99%

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

Anderson

Farin

Bammler

et al. 2011

Journal of Neurotrauma

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“…The suppression of allopregnanolone synthesis increases markers of cell proliferation, an effect that is ameliorated when the synthetic neurosteroid, alfaxalone, is used to replace the loss of the endogenous neurosteroid (Yawno et al 2009). In adult rat models of traumatic brain injury, allopregnanolone administration has also reduced the size of GFAP-positive astrocytes at the site of the experimental lesions (Djebaili et al 2005), and there is increasing evidence for the effectiveness of allopregnanolone in reducing lesion size and enhancing functional recovery in animal models of traumatic brain injury (Djebaili et al 2004, Schumacher et al 2007. In addition to the previously reported neuroprotective actions of allopregnanolone, this study provides evidence of delayed neurodevelopment in the presence of a low neurosteroid environment and suggests an important role of allopregnanolone in the regulation of developmental processes in the late gestation foetal brain.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence that allopregnanolone has a neuroprotective function in both the adult (Djebaili et al 2004, He et al 2004, Schumacher et al 2007) and foetal brains (Yawno et al 2007(Yawno et al , 2009. Inhibition of allopregnanolone synthesis, using finasteride (a 5aR inhibitor), in foetal sheep increased the number of cells undergoing programmed cell death within the brain, and accentuated the cell death caused by asphyxia arising from transient umbilical cord occlusion (Yawno et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

Kelleher¹,

Palliser²,

Walker³

et al. 2010

Journal of Endocrinology

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Progesterone and its neuroactive metabolite, allopregnanolone, are present in high concentrations during pregnancy, but drop significantly following birth. Allopregnanolone influences foetal arousal and enhances cognitive and behavioural recovery following traumatic brain injury. Inhibition of allopregnanolone synthesis increases cell death in foetal animal brains with experimental hypoxia. We hypothesised that complications during pregnancy, such as early or preterm loss of placental steroids and intrauterine growth restriction (IUGR), would disrupt the foetal neurosteroid system, contributing to poor neurodevelopmental outcomes. This study aimed to investigate the effects of chronic inhibition of allopregnanolone synthesis before term and IUGR on developmental processes in the foetal brain. Guinea pig foetuses were experimentally growth restricted at midgestation and treated with finasteride, an inhibitor of allopregnanolone synthesis. Finasteride treatment reduced foetal brain allopregnanolone concentrations by up to 75% and was associated with a reduction in myelin basic protein (MBP) (PZ0 . 001) and an increase in glial fibrillary acidic protein expression in the subcortical white matter brain region (P!0 . 001). IUGR resulted in decreased MBP expression (P!0 . 01) and was associated with a reduction in the expression of steroidogenic enzyme 5a-reductase (5aR) type 2 in the foetal brain (PZ0 . 061). Brain levels of 5aR1 were higher in male foetuses (PZ0 . 008). Both IUGR and reduced foetal brain concentrations of allopregnanolone were associated with altered expression of myelination and glial cell markers within the developing foetal brain. The potential role of neurosteroids in protecting and regulating neurodevelopmental processes in the foetal brain may provide new directions for treatment of neurodevelopmental disorders in infants who are exposed to perinatal insults and pathologies.

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“…19 Perhaps in the present experiments progesterone facilitated the release of trophic factors from nearby Schwann cells. 31,32,[45][46][47] Nerve sectioning plays a fundamental role in aberrant innervation, since it occurred even in animals implanted with silicone tubes. In our study, the synaptic connectivity between the nerve supply to the gastrocnemius muscle and the muscle itself seemed to be functional.…”

Section: Discussionmentioning

confidence: 99%

Aberrant gastrocnemius muscle innervation by tibial nerve afferents after implantation of chitosan tubes impregnated with progesterone favored locomotion recovery in rats with transected sciatic nerve

Sarabia-Estrada

Bañuelos-Pineda

Osuna-Carrasco³

et al. 2015

JNS

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obJect Transection of peripheral nerves produces loss of sensory and/or motor function. After complete nerve cutting, the distal and proximal segment ends retract, but if both ends are bridged with unaltered chitosan, progesteroneimpregnated chitosan, or silicone tubes, an axonal repair process begins. Progesterone promotes nerve repair and has neuroprotective effects thwarting regulation of neuron survival, inflammation, and edema. It also modulates aberrant axonal sprouting and demyelination. The authors compared the efficacy of nerve recovery after implantation of progesterone-loaded chitosan, unaltered chitosan, or silicone tubes after sciatic nerve transection in rats. methods After surgical removal of a 5-mm segment of the proximal sciatic nerve, rats were implanted with progesterone-loaded chitosan, unaltered chitosan, or silicone tubes in the transected nerve for evaluating progesterone and chitosan effects on sciatic nerve repair and ipsilateral hindlimb kinematic function, as well as on gastrocnemius electromyographic responses. In some experiments, tube implantation was performed 90 minutes after nerve transection. results At 90 days after sciatic nerve transection and tube implantation, rats with progesterone-loaded chitosan tubes showed knee angular displacement recovery and better outcomes for step length, velocity of locomotion, and normal hindlimb raising above the ground. In contrast, rats with chitosan-only tubes showed reduced normal raising and pendulum-like hindlimb movements. Aberrant fibers coming from the tibial nerve innervated the gastrocnemius muscle, producing electromyographic responses. Electrical responses in the gastrocnemius muscle produced by sciatic nerve stimulation occurred only when the distal nerve segment was stimulated; they were absent when the proximal or intratubular segment was stimulated. A clear sciatic nerve morphology with some myelinated fiber fascicles appeared in the tube section in rats with progesterone-impregnated chitosan tubes. Some gastrocnemius efferent fibers were partially repaired 90 days after nerve resection. The better outcome in knee angle displacement may be partially attributable to the aberrant neuromuscular synaptic effects, since nerve conduction in the gastrocnemius muscle could be blocked in the progesterone-impregnated chitosan tubes. In addition, in the region of the gap produced by the nerve resection, the number of axons and amount of myelination were reduced in the sciatic nerve implanted with chitosan, progesteroneloaded chitosan, and silicone tubes. At 180 days after sciatic nerve sectioning, the knee kinematic function recovered to a level observed in control rats of a similar age. In rats with progesterone-loaded chitosan tubes, stimulation of the proximal and intratubular sciatic nerve segments produced an electromyographic response. The axon morphology of the proximal and intratubular segments of the sciatic nerve resembled that of the contralateral nontransected nerve. coNclusioNs Progesterone-impregnated chitosan tubes produced...

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Progesterone: Therapeutic opportunities for neuroprotection and myelin repair

Cited by 217 publications

References 443 publications

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

The Effect of Progesterone Dose on Gene Expression after Traumatic Brain Injury

Sex-dependent effect of a low neurosteroid environment and intrauterine growth restriction on fetal guinea pig brain development.

Aberrant gastrocnemius muscle innervation by tibial nerve afferents after implantation of chitosan tubes impregnated with progesterone favored locomotion recovery in rats with transected sciatic nerve

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