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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 hypertension on outcome following MCAO and progesterone treatment. The percentage of animals survived post-surgery over time (A). Mortality data expressed using the Kaplan-Meier curve and analysed using the Mantel-Haenszel log-rank test showed no significant difference between groups in % of surviving animals. All BPH/2 mice significantly lost body mass after surgery (P = 0.0001) but progesterone treatment did not affect the amount of body mass loss (B). Progesterone treatment reduced neurological deficit (C) compared to controls (***P = 0.0001). Contralateral foot-faults (%) were assessed in BPH/2 mice on the day following surgery (D) and there was no difference found between progesterone and non-treated mice (P = 0.0679). Number of animals per group are shown in parentheses and all data (B-D) are expressed as mean ± SEM.
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Fig3: The effect of hypertension on outcome following MCAO and progesterone treatment. The percentage of animals survived post-surgery over time (A). Mortality data expressed using the Kaplan-Meier curve and analysed using the Mantel-Haenszel log-rank test showed no significant difference between groups in % of surviving animals. All BPH/2 mice significantly lost body mass after surgery (P = 0.0001) but progesterone treatment did not affect the amount of body mass loss (B). Progesterone treatment reduced neurological deficit (C) compared to controls (***P = 0.0001). Contralateral foot-faults (%) were assessed in BPH/2 mice on the day following surgery (D) and there was no difference found between progesterone and non-treated mice (P = 0.0679). Number of animals per group are shown in parentheses and all data (B-D) are expressed as mean ± SEM.

Mentions: All progesterone treated animals (five animals) survived to the end of all functional end-points on day seven and one untreated animal died on day three post-surgery (four animals in untreated group prior surgery). Analysis of survival found no significant difference between progesterone and non-treated animals (Figure 3A). All animals lost body mass following surgery [F(1,7) = 13.53, P = <0.0001], but no significant difference was found between groups (Figure 3B). Neurological deficit analysis found progesterone treated mice had significantly lower neurological deficit compared to non-treated animals [F(1,6) = 18.31, P = 0.0001] (Figure 3C). There was no difference in contralateral foot slips between groups in the foot fault test (Figure 3D). Analysis of t-maze tasks found no difference in treatment groups in % alternation rate, but did find progesterone treatment to lower contralateral/ipsilateral alternation ratio % [F(1,2) = 17.05, P = 0.0006] and reduce the time taken to complete trials for T-maze [F(1,2) = 15.92, P = 0.0009] (Table 2). Bonferroni analysis of day 6 shows progesterone treatment significantly increased % left/right ratio (P = <0.05*). Non-treated animals took longer to complete t-maze than progesterone treated animals on days 6 and 7 (P = 0.0009). Bonferroni post-hoc analysis shows day 6 and 7 to be significant (both P = <0.05*).Figure 3


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 hypertension on outcome following MCAO and progesterone treatment. The percentage of animals survived post-surgery over time (A). Mortality data expressed using the Kaplan-Meier curve and analysed using the Mantel-Haenszel log-rank test showed no significant difference between groups in % of surviving animals. All BPH/2 mice significantly lost body mass after surgery (P = 0.0001) but progesterone treatment did not affect the amount of body mass loss (B). Progesterone treatment reduced neurological deficit (C) compared to controls (***P = 0.0001). Contralateral foot-faults (%) were assessed in BPH/2 mice on the day following surgery (D) and there was no difference found between progesterone and non-treated mice (P = 0.0679). Number of animals per group are shown in parentheses and all data (B-D) are expressed as mean ± SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig3: The effect of hypertension on outcome following MCAO and progesterone treatment. The percentage of animals survived post-surgery over time (A). Mortality data expressed using the Kaplan-Meier curve and analysed using the Mantel-Haenszel log-rank test showed no significant difference between groups in % of surviving animals. All BPH/2 mice significantly lost body mass after surgery (P = 0.0001) but progesterone treatment did not affect the amount of body mass loss (B). Progesterone treatment reduced neurological deficit (C) compared to controls (***P = 0.0001). Contralateral foot-faults (%) were assessed in BPH/2 mice on the day following surgery (D) and there was no difference found between progesterone and non-treated mice (P = 0.0679). Number of animals per group are shown in parentheses and all data (B-D) are expressed as mean ± SEM.
Mentions: All progesterone treated animals (five animals) survived to the end of all functional end-points on day seven and one untreated animal died on day three post-surgery (four animals in untreated group prior surgery). Analysis of survival found no significant difference between progesterone and non-treated animals (Figure 3A). All animals lost body mass following surgery [F(1,7) = 13.53, P = <0.0001], but no significant difference was found between groups (Figure 3B). Neurological deficit analysis found progesterone treated mice had significantly lower neurological deficit compared to non-treated animals [F(1,6) = 18.31, P = 0.0001] (Figure 3C). There was no difference in contralateral foot slips between groups in the foot fault test (Figure 3D). Analysis of t-maze tasks found no difference in treatment groups in % alternation rate, but did find progesterone treatment to lower contralateral/ipsilateral alternation ratio % [F(1,2) = 17.05, P = 0.0006] and reduce the time taken to complete trials for T-maze [F(1,2) = 15.92, P = 0.0009] (Table 2). Bonferroni analysis of day 6 shows progesterone treatment significantly increased % left/right ratio (P = <0.05*). Non-treated animals took longer to complete t-maze than progesterone treated animals on days 6 and 7 (P = 0.0009). Bonferroni post-hoc analysis shows day 6 and 7 to be significant (both P = <0.05*).Figure 3

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