Progesterone inhibition of voltage-gated calcium channels is a potential neuroprotective mechanism against excitotoxicity

Luoma, Jessie I.; Kelley, Brooke G.; Mermelstein, P.

doi:10.1016/j.steroids.2011.02.013

Cited by 41 publications

(52 citation statements)

References 60 publications

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“…THP (allopregnanolone), an active metabolite of PROG, has antiapoptotic effects by inhibiting the opening of the permeability transition pore and inhibiting the mitochondrial release of cytochrome c [37]. In cultured neurons of the striatum, PROG blocks neuronal death that occurs by depolarization induced by opening voltage-gated calcium channels by blocking the entry of calcium in these channels [38]. This effect of PROG requires high concentrations and cannot be blocked by the use of a nuclear receptor antagonist, suggesting a mechanism independent of the activation of these receptors [38].…”

Section: Discussionmentioning

confidence: 99%

“…In cultured neurons of the striatum, PROG blocks neuronal death that occurs by depolarization induced by opening voltage-gated calcium channels by blocking the entry of calcium in these channels [38]. This effect of PROG requires high concentrations and cannot be blocked by the use of a nuclear receptor antagonist, suggesting a mechanism independent of the activation of these receptors [38]. PROG increases the activity of Akt and ERK1/2, both major kinases involved in cell survival [12,39].…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

et al. 2015

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Background: Numerous studies have reported on the neuroprotective activity of estradiol, whereas the effect of the other ovarian steroid, progesterone, is much less documented. Methods: This study sought to investigate neuroprotection with a low dose of progesterone (1 µg) in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated male mice to model Parkinson's disease and compare it to the effect of this steroid in intact mice (experiment 1). We also investigated if high doses of progesterone could protect dopaminergic neurons already exposed to MPTP (experiment 2). We measured progesterone effects on various dopaminergic markers [dopamine and its metabolites, dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2)] and on neuroactive steroids in both plasma and the brain. Results: For experiment 1, our results showed that progesterone completely prevented the effect of MPTP toxicity on dopamine concentrations, on the increase in the 3-methoxytyramine/dopamine ratio, as well as on VMAT2-specific binding in the striatum and the substantia nigra. Progesterone decreased MPTP effects on 3,4-dihydroxyphenylacetic acid concentrations and DAT-specific binding in the lateral part of the anterior striatum and in the middle striatum (medial and lateral parts). Progesterone treatment of intact mice had no effect on the markers investigated. For experiment 2, measures of dopaminergic markers in the striatum showed that 8 mg/kg of progesterone was the most effective dose to reduce MPTP effects, and more limited effects were observed with 16 mg/kg. We found that progesterone treatment increases the levels of brain progesterone itself as well as of its metabolites. Conclusion: Our result showed that progesterone has neuroprotective effects on dopaminergic neurons in MPTP-treated male mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

et al. 2015

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“…Inhibition of voltage-gated calcium channels (VGCCs) is a potential neuroprotective mechanism against excitotoxicity [10][11][12], and pregabalin (Lyrica®) could be the key to overcome autoimmune neurodegeneration in diseases like MS. Chemically, pregabalin belongs to the group of gabapentinoids, which are analogues of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) [13], and instead of binding to GABA receptors it binds to two isoforms of the auxiliary α2δ subunit (gene names: Cacna2d1 and Cacna2d2) of VGCCs [14].…”

Section: Introductionmentioning

confidence: 99%

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

Hundehege¹,

Fernández‐Orth²,

Römer³

et al. 2018

Neurosignals

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Background/Aims: Multiple sclerosis (MS) is a prototypical autoimmune central nervous system (CNS) disease. Particularly progressive forms of MS (PMS) show significant neuroaxonal damage as consequence of demyelination and neuronal hyperexcitation. Immuno-modulatory treatment strategies are beneficial in relapsing MS (RMS), but mostly fail in PMS. Pregabalin (Lyrica®) is prescribed to MS patients to treat neuropathic pain. Mechanistically, it targets voltage-dependent Ca²⁺ channels and reduces harmful neuronal hyperexcitation in mouse epilepsy models. Studies suggest that GABA analogues like pregabalin exert neuroprotective effects in animal models of ischemia and trauma. Methods: We tested the impact of pregabalin in a mouse model of MS (experimental autoimmune encephalomyelitis, EAE) and performed histological and immunological evaluations as well as intravital two-photon-microscopy of brainstem EAE lesions. Results: Both prophylactic and therapeutic treatments ameliorated the clinical symptoms of EAE and reduced immune cell infiltration into the CNS. On neuronal level, pregabalin reduced long-term potentiation in hippocampal brain slices indicating an impact on mechanisms of learning and memory. In contrast, T cells, microglia and brain endothelial cells were unaffected by pregabalin. However, we found a direct impact of pregabalin on neurons during CNS inflammation as it reversed the pathological elevation of neuronal intracellular Ca²⁺ levels in EAE lesions. Conclusion: The presented data suggest that pregabalin primarily acts on neuronal Ca²⁺ channel trafficking thereby reducing Ca²⁺-mediated cytotoxicity and neuronal damage in an animal model of MS. Future clinical trials need to assess the benefit for neuronal survival by expanding the indication for pregabalin administration to MS patients in further disease phases.

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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%

“…Sodium voltage-dependent currents are inactivated. 27,31 In this study, we analyzed gastrocnemius muscle electromyography responses produced by sciatic nerve electrical stimulation after implanting progesterone-impregnated chitosan tubes, unaltered chitosan tubes, or silicone tubes in the transected sciatic nerve of the rat. In addition, we analyzed the morphology of the contralateral (control) and ipsilateral sciatic nerve sections.…”

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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 inhibition of voltage-gated calcium channels is a potential neuroprotective mechanism against excitotoxicity

Cited by 41 publications

References 60 publications

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

Neuroprotective Effect of Progesterone in MPTP-Treated Male Mice

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

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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