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Prostaglandin I2 IP Receptor Agonist, Beraprost, Prevents Transient Global Cerebral Ischemia Induced Hippocampal CA1 Injury in Aging Mice.

Shakil H, Saleem S - J Neurol Disord (2014)

Bottom Line: Beraprost reversed BCCAo induced cognitive impairment and neurological deficit in a dose dependent manner.Moreover, after BCCAo, phosphorylated cAMP response element binding protein positive cell numbers were increased with beraprost treatment over vehicle treated controls.These results show that beraprost treatment attenuated cognitive dysfunction and neurological deficits induced by BCCAo, and suggest that this effect may be mediated by the neuroprotective effects of treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Hamdard College of Medicine and Dentistry, Hamdard University, Sharae Madinat Al-Hikmah, Karachi 74600, Pakistan.

ABSTRACT

Beraprost sodium is a new stable, orally active Prostaglandin I2 analogue. The aim of this study was to determine the effect of beraprost on cognitive dysfunction and locomotor impairment induced by bilateral common carotid artery occlusion in mice. We investigated the ameliorating effect of beraprost through PGI2 IP receptor by studying neurologic deficit assessment and T-maze testing in young and old male C57Bl/6 wild-type (WT) and IP receptor knockout (IP KO) mice following a 12 min bilateral common carotid artery occlusion (BCCAo) and 7 days of reperfusion. Beraprost reversed BCCAo induced cognitive impairment and neurological deficit in a dose dependent manner. Immunohistochemical studies showed attenuation of neuronal cell death, astrogliosis, microglial invasion, and myeloperoxidase (MPO) activity in both young and old WT mice after post treatment with beraprost. Moreover, after BCCAo, phosphorylated cAMP response element binding protein positive cell numbers were increased with beraprost treatment over vehicle treated controls. These results show that beraprost treatment attenuated cognitive dysfunction and neurological deficits induced by BCCAo, and suggest that this effect may be mediated by the neuroprotective effects of treatment.

No MeSH data available.


Related in: MedlinePlus

A–D: Phospho-CREB-positive cells are increased after beraprost treatment. (7A and 7C). Representative images of brain sections show p-CREB immunostaining in Young and Old vehicle and beraprost treated (B-25, B-50 and B-100) WT and IP KO ischemic mice. (7B,7D). Cells in the CA1 subfield of the hippocampus were stained for p-CREB after vehicle or beraprost treatment (B-25, B50 and B-100) and quantified on day 7 after ischemia. n=8–10 per group. **P<0.01; ++P<0.01, ××P<0.01 vsIsch Young WT+Veh; P<0.05; **P<0.01, ++P<0.01; XXP<0.01vs Isch Old WT+Veh; n. s.=not significant. Data are presented as mean ± s.e.m.
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Figure 7: A–D: Phospho-CREB-positive cells are increased after beraprost treatment. (7A and 7C). Representative images of brain sections show p-CREB immunostaining in Young and Old vehicle and beraprost treated (B-25, B-50 and B-100) WT and IP KO ischemic mice. (7B,7D). Cells in the CA1 subfield of the hippocampus were stained for p-CREB after vehicle or beraprost treatment (B-25, B50 and B-100) and quantified on day 7 after ischemia. n=8–10 per group. **P<0.01; ++P<0.01, ××P<0.01 vsIsch Young WT+Veh; P<0.05; **P<0.01, ++P<0.01; XXP<0.01vs Isch Old WT+Veh; n. s.=not significant. Data are presented as mean ± s.e.m.

Mentions: Moreover, the old vehicle and beraprost treated C57Bl/6 WT (B-25, B-50 and B-100) (8.9% ± 1.0%; 8.2 ± 1.1; 9.7 ± 1.0; 10.0 ± 0.5% from baseline) and vehicle IP KO and IP KO B-100 treated groups (8.1 ± 1.0; 9.0 ± 0.7% from baseline) showed drop in CBF measured by laser Doppler flowmetry during ischemia and body temperature maintained at 37.0 ± 0.5°C in all the groups. The sham groups (sham vehicle and B-100 treated young and old WT and IP KO) showed not a significant drop in CBF from baseline. Our results show a significant improvement (p<0.01) in locomotor and T-maze activity in both young (2–3 mo.) and old (12–15 mo.) ischemic WT mice as compared to analogous cohorts of IP KO mice after post treatment with beraprost but not vehicle, as shown in Figures 1A,1B,2A and 2B. At day 3, all groups showed similar trends as day 7 (data not shown). While, the sham vehicle and B-100 treated young and old WT and IP KO mice showed no significant change in loco motor activity score (5) and number of no alternations on T-maze score 3–4. Beraprost sodium (25–100 μg/kg b.w. p.o) treatment also dose dependently decreased (p<0.01) neuronal cell death, as measured by the number of cells in the hippocampal CA1 granular layer in both young and old WT mice compared to IP KO counterparts (Figure 3B and 3D). There was no significant difference in NeuN positive cells were observed in sham vehicle and B-100 treated young and old WT and IP KO mice (sham vehicle treated young WT and IP KO 88.0 ± 2.3; 90.2 ± 1.9; sham B-100 treated young WT and IP KO 91.4 ± 2.0; 84.8 ± 2.9; sham vehicle treated old WT and IP KO 88.2 ± 2.4; 84.5 ± 3.2; sham B-100 treated old WT and IP KO 89.5 ± 3.4; 82.0 ± 3.2). Astrogliosis, showed a significant decrease in WT compared to IP KO mice at the highest dose of 100 μg beraprost/kg b.w. (p<0.01). No differences were observed between young and old mice of either genotype (Figure 4B and 4D). Similarly, no astrogliosis was observed in sham vehicle and B-100 treated young and old WT and IP KO mice. Since an immune response follows upon the neuronal death caused by brain ischemia, we assessed activation of microglia and invasion of macrophages (Iba1 staining) and neutrophils, as measures of an immune response. The numbers of microglia/macrophages were reduced by beraprost treatment in a dose-dependent manner (Figure 5B and 5D). Myeloperoxidase is a marker for neutrophils. There was a significant decrease in MPO levels after post treatment with beraprost (Figure 6B and 6D). There were no microglia activation and MPO activity were observed in sham vehicle and B-100 treated young and old WT and IP KO groups. We determined levels of p-CREB since the mechanism of beraprost has been reported to involve the phosphorylation of this important transcription factor. Beraprost treatment results in the up regulated of p-CREB levels in a dose-dependent manner (p<0.01) in young and old WT mice. No significance observed in young and old IP KO vehicle or beraprost treated mice (Figure 7B and 7D). Moreover, there was no up-regulation of p-CREB levels was observed in sham vehicle and B-100 treated young and old WT and IP KO mice.


Prostaglandin I2 IP Receptor Agonist, Beraprost, Prevents Transient Global Cerebral Ischemia Induced Hippocampal CA1 Injury in Aging Mice.

Shakil H, Saleem S - J Neurol Disord (2014)

A–D: Phospho-CREB-positive cells are increased after beraprost treatment. (7A and 7C). Representative images of brain sections show p-CREB immunostaining in Young and Old vehicle and beraprost treated (B-25, B-50 and B-100) WT and IP KO ischemic mice. (7B,7D). Cells in the CA1 subfield of the hippocampus were stained for p-CREB after vehicle or beraprost treatment (B-25, B50 and B-100) and quantified on day 7 after ischemia. n=8–10 per group. **P<0.01; ++P<0.01, ××P<0.01 vsIsch Young WT+Veh; P<0.05; **P<0.01, ++P<0.01; XXP<0.01vs Isch Old WT+Veh; n. s.=not significant. Data are presented as mean ± s.e.m.
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Figure 7: A–D: Phospho-CREB-positive cells are increased after beraprost treatment. (7A and 7C). Representative images of brain sections show p-CREB immunostaining in Young and Old vehicle and beraprost treated (B-25, B-50 and B-100) WT and IP KO ischemic mice. (7B,7D). Cells in the CA1 subfield of the hippocampus were stained for p-CREB after vehicle or beraprost treatment (B-25, B50 and B-100) and quantified on day 7 after ischemia. n=8–10 per group. **P<0.01; ++P<0.01, ××P<0.01 vsIsch Young WT+Veh; P<0.05; **P<0.01, ++P<0.01; XXP<0.01vs Isch Old WT+Veh; n. s.=not significant. Data are presented as mean ± s.e.m.
Mentions: Moreover, the old vehicle and beraprost treated C57Bl/6 WT (B-25, B-50 and B-100) (8.9% ± 1.0%; 8.2 ± 1.1; 9.7 ± 1.0; 10.0 ± 0.5% from baseline) and vehicle IP KO and IP KO B-100 treated groups (8.1 ± 1.0; 9.0 ± 0.7% from baseline) showed drop in CBF measured by laser Doppler flowmetry during ischemia and body temperature maintained at 37.0 ± 0.5°C in all the groups. The sham groups (sham vehicle and B-100 treated young and old WT and IP KO) showed not a significant drop in CBF from baseline. Our results show a significant improvement (p<0.01) in locomotor and T-maze activity in both young (2–3 mo.) and old (12–15 mo.) ischemic WT mice as compared to analogous cohorts of IP KO mice after post treatment with beraprost but not vehicle, as shown in Figures 1A,1B,2A and 2B. At day 3, all groups showed similar trends as day 7 (data not shown). While, the sham vehicle and B-100 treated young and old WT and IP KO mice showed no significant change in loco motor activity score (5) and number of no alternations on T-maze score 3–4. Beraprost sodium (25–100 μg/kg b.w. p.o) treatment also dose dependently decreased (p<0.01) neuronal cell death, as measured by the number of cells in the hippocampal CA1 granular layer in both young and old WT mice compared to IP KO counterparts (Figure 3B and 3D). There was no significant difference in NeuN positive cells were observed in sham vehicle and B-100 treated young and old WT and IP KO mice (sham vehicle treated young WT and IP KO 88.0 ± 2.3; 90.2 ± 1.9; sham B-100 treated young WT and IP KO 91.4 ± 2.0; 84.8 ± 2.9; sham vehicle treated old WT and IP KO 88.2 ± 2.4; 84.5 ± 3.2; sham B-100 treated old WT and IP KO 89.5 ± 3.4; 82.0 ± 3.2). Astrogliosis, showed a significant decrease in WT compared to IP KO mice at the highest dose of 100 μg beraprost/kg b.w. (p<0.01). No differences were observed between young and old mice of either genotype (Figure 4B and 4D). Similarly, no astrogliosis was observed in sham vehicle and B-100 treated young and old WT and IP KO mice. Since an immune response follows upon the neuronal death caused by brain ischemia, we assessed activation of microglia and invasion of macrophages (Iba1 staining) and neutrophils, as measures of an immune response. The numbers of microglia/macrophages were reduced by beraprost treatment in a dose-dependent manner (Figure 5B and 5D). Myeloperoxidase is a marker for neutrophils. There was a significant decrease in MPO levels after post treatment with beraprost (Figure 6B and 6D). There were no microglia activation and MPO activity were observed in sham vehicle and B-100 treated young and old WT and IP KO groups. We determined levels of p-CREB since the mechanism of beraprost has been reported to involve the phosphorylation of this important transcription factor. Beraprost treatment results in the up regulated of p-CREB levels in a dose-dependent manner (p<0.01) in young and old WT mice. No significance observed in young and old IP KO vehicle or beraprost treated mice (Figure 7B and 7D). Moreover, there was no up-regulation of p-CREB levels was observed in sham vehicle and B-100 treated young and old WT and IP KO mice.

Bottom Line: Beraprost reversed BCCAo induced cognitive impairment and neurological deficit in a dose dependent manner.Moreover, after BCCAo, phosphorylated cAMP response element binding protein positive cell numbers were increased with beraprost treatment over vehicle treated controls.These results show that beraprost treatment attenuated cognitive dysfunction and neurological deficits induced by BCCAo, and suggest that this effect may be mediated by the neuroprotective effects of treatment.

View Article: PubMed Central - HTML - PubMed

Affiliation: Hamdard College of Medicine and Dentistry, Hamdard University, Sharae Madinat Al-Hikmah, Karachi 74600, Pakistan.

ABSTRACT

Beraprost sodium is a new stable, orally active Prostaglandin I2 analogue. The aim of this study was to determine the effect of beraprost on cognitive dysfunction and locomotor impairment induced by bilateral common carotid artery occlusion in mice. We investigated the ameliorating effect of beraprost through PGI2 IP receptor by studying neurologic deficit assessment and T-maze testing in young and old male C57Bl/6 wild-type (WT) and IP receptor knockout (IP KO) mice following a 12 min bilateral common carotid artery occlusion (BCCAo) and 7 days of reperfusion. Beraprost reversed BCCAo induced cognitive impairment and neurological deficit in a dose dependent manner. Immunohistochemical studies showed attenuation of neuronal cell death, astrogliosis, microglial invasion, and myeloperoxidase (MPO) activity in both young and old WT mice after post treatment with beraprost. Moreover, after BCCAo, phosphorylated cAMP response element binding protein positive cell numbers were increased with beraprost treatment over vehicle treated controls. These results show that beraprost treatment attenuated cognitive dysfunction and neurological deficits induced by BCCAo, and suggest that this effect may be mediated by the neuroprotective effects of treatment.

No MeSH data available.


Related in: MedlinePlus