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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 aged animals. Comparison of post-surgery survival according to treatment/surgery in aged C57 Bl/6 mice (A). Mortality data expressed using the Kaplan-Meier curve and analysed using the Mantel-Haenszel log-rank test revealed no significant difference between groups in % of surviving animals (P = 0.5266). Body mass gain following surgery in aged C57 Bl/6 mice (B) at 24 h post-MCAO found no difference in body mass gain between progesterone and vehicle treated animals groups (P = 0.8903). Neurological score was assessed in aged C57/Bl6 at 24 h post-MCAO (C) no difference was found between treatment groups. Individual data points are shown for body mass and neurological score.
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Fig2: The effect of progesterone treatment in aged animals. Comparison of post-surgery survival according to treatment/surgery in aged C57 Bl/6 mice (A). Mortality data expressed using the Kaplan-Meier curve and analysed using the Mantel-Haenszel log-rank test revealed no significant difference between groups in % of surviving animals (P = 0.5266). Body mass gain following surgery in aged C57 Bl/6 mice (B) at 24 h post-MCAO found no difference in body mass gain between progesterone and vehicle treated animals groups (P = 0.8903). Neurological score was assessed in aged C57/Bl6 at 24 h post-MCAO (C) no difference was found between treatment groups. Individual data points are shown for body mass and neurological score.

Mentions: Ten aged C57 Bl/6 mice (five progesterone treated and five vehicle treated) were subjected to 30 minutes of occlusion. In the progesterone treated group only one animal survived to the intended end of study, i.e. day 7 post-MCAO, one was found dead the following day after surgery, and 3 were killed for welfare reasons (barrel rolling). The vehicle-treated group comprised two animals surviving to day 7, one found dead the next day after surgery, and two animals killed for welfare (one for barrel rolling after surgery and another on the same day for inability to recover from surgery). There was no difference between treatment groups for overall survival and body mass loss (Figure 2A and B). Also, no difference between treatment groups for neurological deficit score the day after surgery (progesterone n =2, vehicle n =4) was found (Figure 2C).Figure 2


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 aged animals. Comparison of post-surgery survival according to treatment/surgery in aged C57 Bl/6 mice (A). Mortality data expressed using the Kaplan-Meier curve and analysed using the Mantel-Haenszel log-rank test revealed no significant difference between groups in % of surviving animals (P = 0.5266). Body mass gain following surgery in aged C57 Bl/6 mice (B) at 24 h post-MCAO found no difference in body mass gain between progesterone and vehicle treated animals groups (P = 0.8903). Neurological score was assessed in aged C57/Bl6 at 24 h post-MCAO (C) no difference was found between treatment groups. Individual data points are shown for body mass and neurological score.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: The effect of progesterone treatment in aged animals. Comparison of post-surgery survival according to treatment/surgery in aged C57 Bl/6 mice (A). Mortality data expressed using the Kaplan-Meier curve and analysed using the Mantel-Haenszel log-rank test revealed no significant difference between groups in % of surviving animals (P = 0.5266). Body mass gain following surgery in aged C57 Bl/6 mice (B) at 24 h post-MCAO found no difference in body mass gain between progesterone and vehicle treated animals groups (P = 0.8903). Neurological score was assessed in aged C57/Bl6 at 24 h post-MCAO (C) no difference was found between treatment groups. Individual data points are shown for body mass and neurological score.
Mentions: Ten aged C57 Bl/6 mice (five progesterone treated and five vehicle treated) were subjected to 30 minutes of occlusion. In the progesterone treated group only one animal survived to the intended end of study, i.e. day 7 post-MCAO, one was found dead the following day after surgery, and 3 were killed for welfare reasons (barrel rolling). The vehicle-treated group comprised two animals surviving to day 7, one found dead the next day after surgery, and two animals killed for welfare (one for barrel rolling after surgery and another on the same day for inability to recover from surgery). There was no difference between treatment groups for overall survival and body mass loss (Figure 2A and B). Also, no difference between treatment groups for neurological deficit score the day after surgery (progesterone n =2, vehicle n =4) was found (Figure 2C).Figure 2

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