Estrogens in the Treatment of Multiple Sclerosis

Voskuhl, Rhonda R.

doi:10.1007/978-0-387-36003-4_19

Cited by 1 publication

(1 citation statement)

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“…Our study is the first to report that estriol, a pregnancy estrogen, is capable of preventing EAE-mediated impairment hippocampal function and neuropathology. Important evidence from human clinical trials in MS suggest that estriol treatment may be beneficial in clinical application ( 15 , 17 , 69 ) and further investigation in clinical trials is underway ( http://clinicaltrials.gov/ct2/show/NCT00451204 ). This report suggests that estriol treatment should be further investigated for its potential role in preventing hippocampal dysfunction and neuropathology in MS.…”

Section: Discussionmentioning

confidence: 99%

Estriol preserves synaptic transmission in the hippocampus during autoimmune demyelinating disease

Ziehn

Avedisian

Dervin

et al. 2012

Laboratory Investigation

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Cognitive deficits occur in over half of multiple sclerosis patients, with hippocampal-dependent learning and memory commonly impaired. Data from in vivo MRI and post-mortem studies in MS indicate that the hippocampus is targeted. However, the relationship between structural pathology and dysfunction of the hippocampus in MS remains unclear. Hippocampal neuropathology also occurs in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. Although estrogen treatment of EAE has been shown to be anti-inflammatory and neuroprotective in the spinal cord, it is unknown if estrogen treatment may prevent hippocampal pathology and dysfunction. In the current study we examined excitatory synaptic transmission during EAE and focused on pathological changes in synaptic protein complexes known to orchestrate functional synaptic transmission in the hippocampus. We then determined if estriol, a candidate hormone treatment, was capable of preventing functional changes in synaptic transmission and corresponding hippocampal synaptic pathology. Electrophysiological studies revealed altered excitatory synaptic transmission and paired-pulse facilitation (PPF) during EAE. Neuropathological experiments demonstrated that there were decreased levels of pre-and post-synaptic proteins in the hippocampus, diffuse loss of myelin staining and atrophy of the pyramidal layers of hippocampal cornu ammonis 1 (CA1). Estriol treatment prevented decreases in excitatory synaptic transmission and lessened the effect of EAE on PPF. In addition, estriol treatment prevented several neuropathological alterations that occurred in the hippocampus during EAE. Cross-modality correlations revealed that deficits in excitatory synaptic transmission were significantly correlated with reductions in trans-synaptic protein binding partners known to modulate excitatory synaptic transmission. To our knowledge, this is the first report describing a functional correlate to hippocampal neuropathology in any MS model. Furthermore, a treatment was identified that prevented both deficits in synaptic function and hippocampal neuropathology. More than 50% of MS patients experience cognitive deficits, 1,2 and hippocampal-dependent learning and memory is often impaired.3,4 Hippocampal atrophy has been shown in MS patients using in vivo MRI, 5,6 and this atrophy was correlated with impaired performance on visuospatial memory testing, a hippocampal-dependent function.7 Data from postmortem studies in MS have demonstrated that hippocampal demyelination and neuropathology occur. 8,9 This demyelination has been associated with changes in molecules modulating synaptic integrity, axonal transport and glutamate homeostasis.10 Although evidence from both in vivo MRI and post-mortem pathological studies indicates that hippocampal pathology occurs during MS, the relationship between such pathology and dysfunction remains unclear. Moreover, there are currently no treatments available to prevent hippocampal dysfunction during MS.Demyelination, axonal los...

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Section: Discussionmentioning

confidence: 99%