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Estradiol attenuates ischemia-induced death of hippocampal neurons and enhances synaptic transmission in aged, long-term hormone-deprived female rats.

Inagaki T, Kaneko N, Zukin RS, Castillo PE, Etgen AM - PLoS ONE (2012)

Bottom Line: A single dose of E2 (2.25 µg) infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls.Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP) was induced.These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after prolonged periods of hormone withdrawal.

View Article: PubMed Central - PubMed

Affiliation: Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT

Background: Transient global forebrain ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons, and the ovarian hormone 17β-estradiol (E2) reduces neuronal loss in young and middle-aged females. The neuroprotective efficacy of E2 after a prolonged period of hormone deprivation is controversial, and few studies examine this issue in aged animals given E2 treatment after induction of ischemia.

Methodology/principal findings: The present study investigated the neuroprotective effects of E2 administered immediately after global ischemia in aged female rats (15-18 months) after 6 months of hormone deprivation. We also used electrophysiological methods to assess whether CA1 synapses in the aging hippocampus remain responsive to E2 after prolonged hormone withdrawal. Animals were ovariohysterectomized and underwent 10 min global ischemia 6 months later. A single dose of E2 (2.25 µg) infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls. Ischemia also induced moderate loss of CA3/CA4 pyramidal cells. Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP) was induced. The magnitude of LTP and of E2 enhancement of field excitatory postsynaptic potentials was indistinguishable from that recorded in slices from young rats.

Conclusions/significance: The data demonstrate that 1) acute post-ischemic infusion of E2 into the brain ventricles is neuroprotective in aged rats after 6 months of hormone deprivation; and 2) E2 enhances synaptic transmission in CA1 pyramidal neurons of aged long-term hormone deprived females. These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after prolonged periods of hormone withdrawal.

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Global ischemia causes loss of CA3/CA4 pyramidal neurons in aging hippocampusAged female rats were subjected to sham surgery or global ischemia 2 or 6 months after OVX. Because there were no significant differences in cell counts in vehicle (black circles) and E2 (gray circles) treated sham rats, data were combined and shown as a single sham group. Panel A: Surviving CA3 and CA4 pyramidal neurons (250 µm×250 µm) were counted bilaterally in one sector of 4 sections of the dorsal hippocampus (top panel). Representative photomicrographs of neurons in the CA3 and CA4 subfield in sham (middle panel) and ischemia+vehicle (bottom panel) groups. Panel B: Surviving CA3 (left) and CA4 (right) neurons in females OVX for 6 months and assessed at 1 week after sham or ischemia surgery and treated intraventricularly with vehicle or 2.25 µg of E2. Panel C: Surviving CA3 (left) and CA4 (right) neurons in females OVX for 2 months and assessed 1 week after sham or ischemia surgery and treated intraventricularly with vehicle or 2.25 µg of E2. Data are means ± SEM. *, p<0.05 versus sham.
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pone-0038018-g003: Global ischemia causes loss of CA3/CA4 pyramidal neurons in aging hippocampusAged female rats were subjected to sham surgery or global ischemia 2 or 6 months after OVX. Because there were no significant differences in cell counts in vehicle (black circles) and E2 (gray circles) treated sham rats, data were combined and shown as a single sham group. Panel A: Surviving CA3 and CA4 pyramidal neurons (250 µm×250 µm) were counted bilaterally in one sector of 4 sections of the dorsal hippocampus (top panel). Representative photomicrographs of neurons in the CA3 and CA4 subfield in sham (middle panel) and ischemia+vehicle (bottom panel) groups. Panel B: Surviving CA3 (left) and CA4 (right) neurons in females OVX for 6 months and assessed at 1 week after sham or ischemia surgery and treated intraventricularly with vehicle or 2.25 µg of E2. Panel C: Surviving CA3 (left) and CA4 (right) neurons in females OVX for 2 months and assessed 1 week after sham or ischemia surgery and treated intraventricularly with vehicle or 2.25 µg of E2. Data are means ± SEM. *, p<0.05 versus sham.

Mentions: We observed substantial CA3 and CA4 cell loss in some sections from 6 month OVX animals subjected to global ischemia. As shown in Fig.3, ischemia produced moderate (about 30% compared to sham), but significant pyramidal cell loss in vehicle-treated ischemic animals in both CA3 (F = 7.13, p<0.01) and CA4 (F = 5.86, p<0.05) areas. There were no differences in cell counts in vehicle- and E2-treated sham rats in CA3 (z = −0.37, p = 0.73) or CA4 (z = −0.25, p = 0.91). Thus, sham data were combined and used for post-hoc tests. Infusion of E2 tended to reduce neuronal loss to about 10–15%, but the effect of E2 was not statistically significant (Fig. 3B). To determine whether CA3/CA4 cells are vulnerable to ischemia in middle-aged females subjected to shorter periods of hormone deprivation, we counted CA3 and CA4 pyramidal cells from middle-aged, retired breeders subjected to ischemia or sham surgery 2 months after OVX and treated intraventricularly with vehicle or E2 as described in Methods. Ischemia did not affect CA4 cell counts (F = 2.18, p<0.15), but significantly reduced CA3 pyramidal neurons (about 12% cell loss, F = 6.13, p<0.05) in these animals (Fig. 3C). There was a tendency for E2 to attenuate CA3 pyramidal cell death in ischemic rats, but the effect was not significant.


Estradiol attenuates ischemia-induced death of hippocampal neurons and enhances synaptic transmission in aged, long-term hormone-deprived female rats.

Inagaki T, Kaneko N, Zukin RS, Castillo PE, Etgen AM - PLoS ONE (2012)

Global ischemia causes loss of CA3/CA4 pyramidal neurons in aging hippocampusAged female rats were subjected to sham surgery or global ischemia 2 or 6 months after OVX. Because there were no significant differences in cell counts in vehicle (black circles) and E2 (gray circles) treated sham rats, data were combined and shown as a single sham group. Panel A: Surviving CA3 and CA4 pyramidal neurons (250 µm×250 µm) were counted bilaterally in one sector of 4 sections of the dorsal hippocampus (top panel). Representative photomicrographs of neurons in the CA3 and CA4 subfield in sham (middle panel) and ischemia+vehicle (bottom panel) groups. Panel B: Surviving CA3 (left) and CA4 (right) neurons in females OVX for 6 months and assessed at 1 week after sham or ischemia surgery and treated intraventricularly with vehicle or 2.25 µg of E2. Panel C: Surviving CA3 (left) and CA4 (right) neurons in females OVX for 2 months and assessed 1 week after sham or ischemia surgery and treated intraventricularly with vehicle or 2.25 µg of E2. Data are means ± SEM. *, p<0.05 versus sham.
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Related In: Results  -  Collection

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pone-0038018-g003: Global ischemia causes loss of CA3/CA4 pyramidal neurons in aging hippocampusAged female rats were subjected to sham surgery or global ischemia 2 or 6 months after OVX. Because there were no significant differences in cell counts in vehicle (black circles) and E2 (gray circles) treated sham rats, data were combined and shown as a single sham group. Panel A: Surviving CA3 and CA4 pyramidal neurons (250 µm×250 µm) were counted bilaterally in one sector of 4 sections of the dorsal hippocampus (top panel). Representative photomicrographs of neurons in the CA3 and CA4 subfield in sham (middle panel) and ischemia+vehicle (bottom panel) groups. Panel B: Surviving CA3 (left) and CA4 (right) neurons in females OVX for 6 months and assessed at 1 week after sham or ischemia surgery and treated intraventricularly with vehicle or 2.25 µg of E2. Panel C: Surviving CA3 (left) and CA4 (right) neurons in females OVX for 2 months and assessed 1 week after sham or ischemia surgery and treated intraventricularly with vehicle or 2.25 µg of E2. Data are means ± SEM. *, p<0.05 versus sham.
Mentions: We observed substantial CA3 and CA4 cell loss in some sections from 6 month OVX animals subjected to global ischemia. As shown in Fig.3, ischemia produced moderate (about 30% compared to sham), but significant pyramidal cell loss in vehicle-treated ischemic animals in both CA3 (F = 7.13, p<0.01) and CA4 (F = 5.86, p<0.05) areas. There were no differences in cell counts in vehicle- and E2-treated sham rats in CA3 (z = −0.37, p = 0.73) or CA4 (z = −0.25, p = 0.91). Thus, sham data were combined and used for post-hoc tests. Infusion of E2 tended to reduce neuronal loss to about 10–15%, but the effect of E2 was not statistically significant (Fig. 3B). To determine whether CA3/CA4 cells are vulnerable to ischemia in middle-aged females subjected to shorter periods of hormone deprivation, we counted CA3 and CA4 pyramidal cells from middle-aged, retired breeders subjected to ischemia or sham surgery 2 months after OVX and treated intraventricularly with vehicle or E2 as described in Methods. Ischemia did not affect CA4 cell counts (F = 2.18, p<0.15), but significantly reduced CA3 pyramidal neurons (about 12% cell loss, F = 6.13, p<0.05) in these animals (Fig. 3C). There was a tendency for E2 to attenuate CA3 pyramidal cell death in ischemic rats, but the effect was not significant.

Bottom Line: A single dose of E2 (2.25 µg) infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls.Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP) was induced.These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after prolonged periods of hormone withdrawal.

View Article: PubMed Central - PubMed

Affiliation: Dominick P Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT

Background: Transient global forebrain ischemia causes selective, delayed death of hippocampal CA1 pyramidal neurons, and the ovarian hormone 17β-estradiol (E2) reduces neuronal loss in young and middle-aged females. The neuroprotective efficacy of E2 after a prolonged period of hormone deprivation is controversial, and few studies examine this issue in aged animals given E2 treatment after induction of ischemia.

Methodology/principal findings: The present study investigated the neuroprotective effects of E2 administered immediately after global ischemia in aged female rats (15-18 months) after 6 months of hormone deprivation. We also used electrophysiological methods to assess whether CA1 synapses in the aging hippocampus remain responsive to E2 after prolonged hormone withdrawal. Animals were ovariohysterectomized and underwent 10 min global ischemia 6 months later. A single dose of E2 (2.25 µg) infused intraventricularly after reperfusion significantly increased cell survival, with 45% of CA1 neurons surviving vs 15% in controls. Ischemia also induced moderate loss of CA3/CA4 pyramidal cells. Bath application of 1 nM E2 onto brain slices derived from non-ischemic aged females after 6 months of hormone withdrawal significantly enhanced excitatory transmission at CA1 synapses evoked by Schaffer collateral stimulation, and normal long-term potentiation (LTP) was induced. The magnitude of LTP and of E2 enhancement of field excitatory postsynaptic potentials was indistinguishable from that recorded in slices from young rats.

Conclusions/significance: The data demonstrate that 1) acute post-ischemic infusion of E2 into the brain ventricles is neuroprotective in aged rats after 6 months of hormone deprivation; and 2) E2 enhances synaptic transmission in CA1 pyramidal neurons of aged long-term hormone deprived females. These findings provide evidence that the aging hippocampus remains responsive to E2 administered either in vivo or in vitro even after prolonged periods of hormone withdrawal.

Show MeSH
Related in: MedlinePlus