ReviewProgesterone's role in neuroprotection, a review of the evidence
Introduction
Over the last 25 years multiple investigators have explored the role of progesterone (PROG) in the treatment of neurologic disease. Interest in the hormone was initially sparked by Attella et al. (1987), who observed improved functional outcomes and decreased edema in pseudopregnant rats suffering from traumatic brain injury (TBI) compared to normal-cycling females with similar injuries. The investigators speculated that the observed difference could be attributed to higher levels of gonadal hormones in the pseudopregnant state. Follow-up studies by Roof et al. (Roof et al., 1992, Roof et al., 1993a, Roof et al., 1994) confirmed that administration of PROG could attenuate cerebral edema and improve functional outcomes in both male and female rats subjected to TBI, providing a framework for future research.
Numerous other papers have demonstrated neuroprotective effects of PROG in TBI and other neurologic conditions including ischemia, spinal cord injury, peripheral nerve injury, motorneuron disease, demyelinating disease, and seizures. We present a comprehensive overview of the in vivo animal research to date pertaining to the administration of PROG in neurologic disease. Within each disease family we review the animal models used, the documented functional changes attributed to PROG (Fig. 1), the mechanisms through which PROG has been hypothesized to act (Table 1), and the effect of variable treatment protocols (e.g. administration site/method, dose, window of treatment, and use of related hormones). The collected body of work provides compelling evidence for the trial of PROG for neurologic disease in humans.
Section snippets
Animal models
TBI was the first neurologic disease for which PROG administration was studied, and remains one of the most studied to date. Several animal models have been used to simulate TBI, the vast majority of which were performed in rats. The initial Attella et al. (1987) study used a bilateral medial frontal cortex (bMFC) ablation model. Ablation injuries involve partial craniotomy and aspiration of the brain parenchyma. Similar injuries in other studies have been produced in the bilateral medial
Animal models
Ischemia has been studied extensively using a number of animal models. By far the most utilized model has been middle cerebral artery occlusion (MCAO), usually by the insertion of an intraluminal filament. The common, internal, and external carotid arteries are exposed and the filament is advanced up the lumen of the ICA until it blocks the origin of the MCA, occluding blood flow. Several studies used this method to induce transient ischemia (tMCAO), placing the filament for a given amount of
Animal models
Animal models for spinal cord injury (SCI) are more limited than those for TBI or ischemia; however, a few have been used to examine the effect of PROG. Some researchers have used blunt force to create SCI. Two studies created spinal cord contusion by removing the spinous processes and lamina and dropping an impactor onto the exposed dura (Fee et al., 2007, Thomas et al., 1999). SCI has also been induced via transient application of aneurysm clips to the exposed spinal cord in the thoracic
Animal models
Several models have been used to study the effect of PROG on peripheral nerve injury. Yu et al. (1989) transected both the hypoglossal and facial nerves to study PROGs effects. Other studies have injured the sciatic nerve using cryolesion (Koenig et al., 1995), crush injury by transient clamp compression (Roglio et al., 2008), cuff application (Dableh and Henry, 2011), or single ligature nerve constriction (Coronel et al., 2011a). Docetaxel has also been infused intravenously to produce a
Animal models
The effects of PROG on demyelinating diseases such as multiple sclerosis (MS) have been studied using a few different animal models. Demyelination of areas of either the central or peripheral nervous system have been induced by localized injection of the toxins ethidium bromide (Ibanez et al., 2004), lysophospatidylcholine (LPC) (Garay et al., 2011), and lysophosphatidic acid (LPA) (Kim et al., 2012). More diffuse demyelination is seen in the experimental autoimmune encephalitis (EAE) model (
Animal models
Research on the use of PROG for motorneuron disease has been done exclusively in Wobbler mice (Deniselle et al., 2012, Gonzalez Deniselle et al., 2002a, Gonzalez Deniselle et al., 2002b, Gonzalez Deniselle et al., 2004, Gonzalez Deniselle et al., 2005, Meyer et al., 2010, Meyer et al., 2013). The Wobbler mouse has a mutation of the autosomal recessive wr gene that results in motorneuron degeneration in the spinal cord and brain stem. This produces a disease process similar to the human
Animal models
Extensive research has been done evaluating the effect of PROG on seizures. The majority of studies have used toxin-induced seizure models in either mice or rats. Toxins administered have included kainic acid (Frye and Bayon, 1999, Frye and Scalise, 2000, Frye and Walf, 2011, Hoffman et al., 2003, Kokate et al., 1996, Nicoletti et al., 1985), bicuculline (Belelli et al., 1989, Czlonkowska et al., 2000), metrazol (Belelli et al., 1989), picrotoxin (Belelli et al., 1989, Czlonkowska et al., 2000,
Animal models
Progesterone and its metabolites have also been evaluated for the treatment of Alzheimer’s Disease (AD). Transgenic mice have been utilized in several studies to model AD. Some studies have utilized mice that co-overexpress a mutant form of amyloid precursor protein and a deletion in presenilin 1 Δ exon 9 (APPswe+PSED1Δe9) (Bengtsson et al., 2012, Frye and Walf, 2008, Frye and Walf, 2009). Others used a triple transgenic mouse model (3xTg-AD), with PS1(M146V), APP(Swe), and tau(P301L)
Other neurologic diseases
More limited work has been done on PROG use in a number of other neurologic diseases. Limmroth et al. studied the effect of PROG on meningeal edema (Limmroth et al., 1996). Edema was generated via electrical stimulation of the trigeminal ganglion. PROG and its metabolites (ALLO, tetrahydroxydeoxycorticosterone, and synthetic alphaxalone) were found to reduce plasma extravasation via GABAA receptors. They speculated that PROG may therefore be clinically effective in the treatment of migraine and
Discussion
In 1999 the Stroke Therapy Academic Industry Roundtable (STAIR) set out to develop a set of recommendations to guide the preclinical study of a potential drug therapy prior to clinical trials (Feinklestein et al., 1999). Although the guidelines were developed with treatment of stroke in mind, the general principles may be applied to other neurologic disease. Their recommendations were as follows: adequate dose-response curve; define the time window in a well-characterized model; blinded,
Contributions
DWW conceived and initiated the review. ERD participated in the literature review, assisted with study interpretation, prepared the first draft and final draft. TRE, FA, EW, JK, and DWW assisted with the literature review, data interpretation, editing drafts, and contributed significantly to manuscript preparation.
Acknowledgments
We would like to thank Dr. Donald Stein and Ms. Leslie McCann for their review and editing of the manuscript.
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