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Evaluating the translational potential of progesterone treatment following transient cerebral ischaemia in male mice.

Wong R, Gibson CL, Kendall DA, Bath PM - BMC Neurosci (2014)

Bottom Line: The aim of this study was two-fold; firstly, we aimed to determine whether progesterone delivery via osmotic mini-pump would confer neuroprotective effects and whether such neuroprotection could be produced in co-morbid animals.Progesterone reduced neurological deficit [F(1,2) = 5.38, P = 0.027] and number of contralateral foot-faults [F(1,2) = 7.36, P = 0.0108] in adult, but not aged animals, following ischaemia.However, in hypertensive mice, who received post-ischemic progesterone intraperitoneally at the onset of reperfusion had better functional outcomes than control hypertensive mice.

View Article: PubMed Central - PubMed

Affiliation: School of Psychology, University of Leicester, Henry Wellcome Building, Leicester LE1 9HN, UK. cg95@le.ac.uk.

ABSTRACT

Background: Progesterone is neuroprotective in numerous preclinical CNS injury models including cerebral ischaemia. The aim of this study was two-fold; firstly, we aimed to determine whether progesterone delivery via osmotic mini-pump would confer neuroprotective effects and whether such neuroprotection could be produced in co-morbid animals.

Results: Animals underwent transient middle cerebral artery occlusion. At the onset of reperfusion, mice were injected intraperitoneally with progesterone (8 mg/kg in dimethylsulfoxide). Adult and aged C57 Bl/6 mice were dosed additionally with subcutaneous infusion (1.0 μl/h of a 50 mg/ml progesterone solution) via implanted osmotic minipumps. Mice were allowed to survive for up to 7 days post-ischaemia and assessed for general well-being (mass loss and survival), neurological score, foot fault and t-maze performance. Progesterone reduced neurological deficit [F(1,2) = 5.38, P = 0.027] and number of contralateral foot-faults [F(1,2) = 7.36, P = 0.0108] in adult, but not aged animals, following ischaemia. In hypertensive animals, progesterone treatment lowered neurological deficit [F(1,6) = 18.31, P = 0.0001], reduced contralateral/ipsilateral alternation ratio % [F(1,2) = 17.05, P = 0.0006] and time taken to complete trials [F(1,2) = 15.92, P = 0.0009] for t-maze.

Conclusion: Post-ischemic progesterone administration via mini-pump delivery is effective in conferring functional improvement in a transient MCAO model in adult mice. Preliminary data suggests such a treatment regimen was not effective in producing a protective effect in aged mice. However, in hypertensive mice, who received post-ischemic progesterone intraperitoneally at the onset of reperfusion had better functional outcomes than control hypertensive mice.

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The effect of progesterone treatment in young adult males. Comparison of post-surgery survival according to treatment/surgery (A). Mortality data expressed using the Kaplan-Meier curve and analysis using the Mantel-Haenszel log-rank test revealed no significant difference in survival between groups (P = 0.3286). In terms of body mass gain following surgery (B), both progesterone and vehicle treated groups gained body mass at significantly slower rate compared to shams (P = 0.0004). Neurological deficit scoring (C) revealed that MCAO resulted in a significant neurological deficit regardless of whether mice had received progesterone (P = 0.0049) or vehicle (P = 0.0002) treatment compared to shams. Progesterone treatment reduced neurological deficit compared to vehicle treatment (P = 0.0271). Assessment of motor performance, using the foot-fault test (D) revealed that progesterone treatment resulted in significantly fewer contralateral foot-faults compared to vehicle treated animals (P = 0.0108). Number of animals per group is shown in parentheses, all data (B-D) are expressed as mean ± SEM, and * = P < 0.05.
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Fig1: The effect of progesterone treatment in young adult males. Comparison of post-surgery survival according to treatment/surgery (A). Mortality data expressed using the Kaplan-Meier curve and analysis using the Mantel-Haenszel log-rank test revealed no significant difference in survival between groups (P = 0.3286). In terms of body mass gain following surgery (B), both progesterone and vehicle treated groups gained body mass at significantly slower rate compared to shams (P = 0.0004). Neurological deficit scoring (C) revealed that MCAO resulted in a significant neurological deficit regardless of whether mice had received progesterone (P = 0.0049) or vehicle (P = 0.0002) treatment compared to shams. Progesterone treatment reduced neurological deficit compared to vehicle treatment (P = 0.0271). Assessment of motor performance, using the foot-fault test (D) revealed that progesterone treatment resulted in significantly fewer contralateral foot-faults compared to vehicle treated animals (P = 0.0108). Number of animals per group is shown in parentheses, all data (B-D) are expressed as mean ± SEM, and * = P < 0.05.

Mentions: During the post-operative period a number of animals were sacrificed for welfare reasons; 1 sham-operated mouse (>20% body mass loss), 6 vehicle-treated animals (4 for >20% body mass loss, 2 for barrel rolling), and 5 progesterone-treated animals (1 > 20% body mass loss, 3 for barrel rolling and one found dead the day following surgery). Analysis of survival data revealed no significant differences in survival rate between treatment groups (P = 0.3286, Figure 1A). Table 1 shows the number of animals in each experimental group at each time point. All animals lost body mass for the first few days following either MCAO or sham surgery before beginning to gain body mass. Both the progesterone- [F(1,7) = 27.03, P = 0.0001] and vehicle-treated [F(1,7) = 13.79, P = 0.0004] groups gained body mass at a significantly slower rate compared to shams. There were no significant differences in body body mass gain between the progesterone and vehicle treated groups [F(1,7) = 1.23, P = 0.2699] (Figure 1B).Figure 1


Evaluating the translational potential of progesterone treatment following transient cerebral ischaemia in male mice.

Wong R, Gibson CL, Kendall DA, Bath PM - BMC Neurosci (2014)

The effect of progesterone treatment in young adult males. Comparison of post-surgery survival according to treatment/surgery (A). Mortality data expressed using the Kaplan-Meier curve and analysis using the Mantel-Haenszel log-rank test revealed no significant difference in survival between groups (P = 0.3286). In terms of body mass gain following surgery (B), both progesterone and vehicle treated groups gained body mass at significantly slower rate compared to shams (P = 0.0004). Neurological deficit scoring (C) revealed that MCAO resulted in a significant neurological deficit regardless of whether mice had received progesterone (P = 0.0049) or vehicle (P = 0.0002) treatment compared to shams. Progesterone treatment reduced neurological deficit compared to vehicle treatment (P = 0.0271). Assessment of motor performance, using the foot-fault test (D) revealed that progesterone treatment resulted in significantly fewer contralateral foot-faults compared to vehicle treated animals (P = 0.0108). Number of animals per group is shown in parentheses, all data (B-D) are expressed as mean ± SEM, and * = P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4255926&req=5

Fig1: The effect of progesterone treatment in young adult males. Comparison of post-surgery survival according to treatment/surgery (A). Mortality data expressed using the Kaplan-Meier curve and analysis using the Mantel-Haenszel log-rank test revealed no significant difference in survival between groups (P = 0.3286). In terms of body mass gain following surgery (B), both progesterone and vehicle treated groups gained body mass at significantly slower rate compared to shams (P = 0.0004). Neurological deficit scoring (C) revealed that MCAO resulted in a significant neurological deficit regardless of whether mice had received progesterone (P = 0.0049) or vehicle (P = 0.0002) treatment compared to shams. Progesterone treatment reduced neurological deficit compared to vehicle treatment (P = 0.0271). Assessment of motor performance, using the foot-fault test (D) revealed that progesterone treatment resulted in significantly fewer contralateral foot-faults compared to vehicle treated animals (P = 0.0108). Number of animals per group is shown in parentheses, all data (B-D) are expressed as mean ± SEM, and * = P < 0.05.
Mentions: During the post-operative period a number of animals were sacrificed for welfare reasons; 1 sham-operated mouse (>20% body mass loss), 6 vehicle-treated animals (4 for >20% body mass loss, 2 for barrel rolling), and 5 progesterone-treated animals (1 > 20% body mass loss, 3 for barrel rolling and one found dead the day following surgery). Analysis of survival data revealed no significant differences in survival rate between treatment groups (P = 0.3286, Figure 1A). Table 1 shows the number of animals in each experimental group at each time point. All animals lost body mass for the first few days following either MCAO or sham surgery before beginning to gain body mass. Both the progesterone- [F(1,7) = 27.03, P = 0.0001] and vehicle-treated [F(1,7) = 13.79, P = 0.0004] groups gained body mass at a significantly slower rate compared to shams. There were no significant differences in body body mass gain between the progesterone and vehicle treated groups [F(1,7) = 1.23, P = 0.2699] (Figure 1B).Figure 1

Bottom Line: The aim of this study was two-fold; firstly, we aimed to determine whether progesterone delivery via osmotic mini-pump would confer neuroprotective effects and whether such neuroprotection could be produced in co-morbid animals.Progesterone reduced neurological deficit [F(1,2) = 5.38, P = 0.027] and number of contralateral foot-faults [F(1,2) = 7.36, P = 0.0108] in adult, but not aged animals, following ischaemia.However, in hypertensive mice, who received post-ischemic progesterone intraperitoneally at the onset of reperfusion had better functional outcomes than control hypertensive mice.

View Article: PubMed Central - PubMed

Affiliation: School of Psychology, University of Leicester, Henry Wellcome Building, Leicester LE1 9HN, UK. cg95@le.ac.uk.

ABSTRACT

Background: Progesterone is neuroprotective in numerous preclinical CNS injury models including cerebral ischaemia. The aim of this study was two-fold; firstly, we aimed to determine whether progesterone delivery via osmotic mini-pump would confer neuroprotective effects and whether such neuroprotection could be produced in co-morbid animals.

Results: Animals underwent transient middle cerebral artery occlusion. At the onset of reperfusion, mice were injected intraperitoneally with progesterone (8 mg/kg in dimethylsulfoxide). Adult and aged C57 Bl/6 mice were dosed additionally with subcutaneous infusion (1.0 μl/h of a 50 mg/ml progesterone solution) via implanted osmotic minipumps. Mice were allowed to survive for up to 7 days post-ischaemia and assessed for general well-being (mass loss and survival), neurological score, foot fault and t-maze performance. Progesterone reduced neurological deficit [F(1,2) = 5.38, P = 0.027] and number of contralateral foot-faults [F(1,2) = 7.36, P = 0.0108] in adult, but not aged animals, following ischaemia. In hypertensive animals, progesterone treatment lowered neurological deficit [F(1,6) = 18.31, P = 0.0001], reduced contralateral/ipsilateral alternation ratio % [F(1,2) = 17.05, P = 0.0006] and time taken to complete trials [F(1,2) = 15.92, P = 0.0009] for t-maze.

Conclusion: Post-ischemic progesterone administration via mini-pump delivery is effective in conferring functional improvement in a transient MCAO model in adult mice. Preliminary data suggests such a treatment regimen was not effective in producing a protective effect in aged mice. However, in hypertensive mice, who received post-ischemic progesterone intraperitoneally at the onset of reperfusion had better functional outcomes than control hypertensive mice.

Show MeSH
Related in: MedlinePlus