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Progesterone in transient ischemic stroke: a dose–response study

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Abstract

Rationale

Previous studies demonstrate the neuroprotective effects of progesterone in numerous animal injury models, but a systematic dose–response study in a transient ischemic stroke model is lacking.

Objectives

We investigated the effects of progesterone at different doses on post-stroke brain infarction and functional deficits in middle-aged rats.

Methods

Cerebral ischemia was induced in 13-month-old male Sprague–Dawley rats by right middle cerebral artery occlusion for 2 h followed by reperfusion. Rats received intraperitoneal injections of 8, 16, or 32 mg/kg of progesterone (P8, P16, P32) or vehicle at 2 h post-occlusion followed by subcutaneous injections at 6 h and every 24 h post-injury for 7 days. Functional recovery was evaluated at intervals over 22 days using motor, sensory, and cognitive tests. Infarct size was evaluated at 22 days post-stroke.

Results

Repeated-measures ANOVA showed significant group effects on grip strength, rotarod, and sensory neglect. All progesterone-treated groups had improved (p < 0.05) spatial memory performance. The P8 and P16 groups showed maximum improvement in long-term memory compared to vehicle. Significant (p < 0.05) gait impairments were observed in the vehicle group compared to shams. Animals receiving the P8 dose showed maximum gait improvement compared to vehicle. Post hoc analysis revealed that the P8 and P16 groups showed significant attenuation in infarct volume compared to vehicle. Animals receiving the P32 dose did not show any effect on infarct volume.

Conclusions

Although all doses were somewhat effective, progesterone given at 8 mg/kg led to the most consistent improvements across a panel of behavioral/functional tests and reduced the severity of ischemic infarct injury.

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Acknowledgements

This research was supported by a NIH award U01 NS062676, BHR Pharma, and Allen and Company. The authors would like to thank Leslie McCann for her invaluable editorial assistance. SY is thankful to Jun Wang for his assistance in brain histology.

Conflict of interest

DGS is entitled to royalties from products of BHR Pharma LLC (BHR) related to the use of PROG in TBI and stroke, and may receive research funding from BHR, which is developing products related to this research. In addition, he serves as a consultant to BHR and receives compensation for these services. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.

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  1. Department of Emergency Medicine, Brain Research Laboratory, Emory University, 1365B Clifton Road NE, Suite 5100, Atlanta, GA, 30322, USA

    Seema Yousuf, Fahim Atif, Iqbal Sayeed, Huiling Tang & Donald G. Stein

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  1. Seema Yousuf
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  2. Fahim Atif
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  5. Donald G. Stein
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Correspondence to Seema Yousuf.

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Yousuf, S., Atif, F., Sayeed, I. et al. Progesterone in transient ischemic stroke: a dose–response study. Psychopharmacology 231, 3313–3323 (2014). https://doi.org/10.1007/s00213-014-3556-8

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  • DOI: https://doi.org/10.1007/s00213-014-3556-8

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