Elsevier

Neuroscience

Volume 123, Issue 2, 2004, Pages 349-359
Neuroscience

Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat pre-frontal cortex

https://doi.org/10.1016/j.neuroscience.2003.09.023Get rights and content

Abstract

We compared the effects of three different doses of allopregnanolone (4, 8 or 16 mg/kg), a metabolite of progesterone, to progesterone (16 mg/kg) in adult rats with controlled cortical impact to the pre-frontal cortex. Injections were given 1 h, 6 h and every day for 5 consecutive days after the injury. One day after injury, both progesterone-treated (16 mg/kg) and allopregnanolone (8 or 16 mg/kg)-treated rats showed less caspase-3 activity, and rats treated with allopregnanolone (16 mg/kg) showed less DNA fragmentation in the lesion area, indicating reduced apoptosis. Nineteen days after the injury, rats treated with progesterone and allopregnanolone (8 or 16 mg/kg) showed no difference in necrotic cavity size but had less cell loss in the medio-dorsal nucleus of the thalamus and less learning and memory impairments compared with the injured vehicle-treated rats. On that same day the injured rats treated with progesterone showed more weight gain compared with the injured rats treated with the vehicle. These results can be taken to show that progesterone and allopregnanolone have similar neuroprotective effects after traumatic brain injury, but allopregnanolone appears to be more potent than progesterone in facilitating CNS repair.

Section snippets

Animals

A total of 48 adult male Sprague-Dawley rats weighing approximately 280–350 g served as subjects. All procedures involving animals conformed to guidelines set forth in the “Guide for the Care and Use of Laboratory Animals” (National Academy of Sciences, 1996) and were approved by the Emory University Institutional Animal Care and Use Committee (IACUC of Emory University protocol 101–99). Approved protocols meeting NIH guidelines require that investigators take all necessary steps to minimize

Neurosteroid effect on caspase-3 activity at the lesion site

Twenty-four hours after injury, logarithm transfor-mation of caspase-3 activity data showed a significant difference among groups (F(5,35)=3.583, P<0.05) and injured rats given vehicle or ALLOP (4 mg/kg) were the only ones to show significantly higher caspase-3 activity compared with shams (P<0.05; Table 1).

Neurosteroid effect on DNA fragmentation

One day after the injury, post hoc tests failed to show a significant difference between groups (F(5,17)=2.452, P=0.094). No significant difference between shams and lesion rats given

Discussion

These results suggest, in general, that ALLOP and PROG produce long-term memory improvements after a bilateral injury to the pre-frontal cortex in rats. In addition, animals treated with either neurosteroid at 24 h post-injury showed a decrease of caspase-3 activity, and at 19 days after the injury, a decrease of cell death in the MDN of the thalamus, a region distal to the lesion site. Generally, rats given ALLOP (8 mg/kg) were similar in performance to their sham-operated counterparts. The

Acknowledgements

This work was supported by NIH grants 1 R01 NS40825, 1 R01 NS38664, and a gift from GeneralCologneRe.

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