Limits...
Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

Freeman BD, Martins YC, Akide-Ndunge OB, Bruno FP, Wang H, Tanowitz HB, Spray DC, Desruisseaux MS - PLoS Pathog. (2016)

Bottom Line: Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival.ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion.This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT
Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

Show MeSH

Related in: MedlinePlus

ET-1 induces cognitive dysfunction in non-CM mice.Visual memory testing was performed on PbN-infected (non-CM) and PbN-infected ET-1 treated mice. Non-CM mice do not display visual memory impairments (A,B). (B) A significantly higher proportion of PbN mice passed the object recognition test when compared to PbA mice (p < 0.0001). (A) Exogenous ET-1 treatment induced cognitive dysfunction in PbN-infected mice (p < 0.05). (B) In addition, PbN ET-1 treated mice performed significantly worse than PbN saline treated mice (p < 0.0001). One-way ANOVA was performed for preference scores in A, and Chi-square was performed for success rate in B. n = 4–20/group.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4816336&req=5

ppat.1005477.g009: ET-1 induces cognitive dysfunction in non-CM mice.Visual memory testing was performed on PbN-infected (non-CM) and PbN-infected ET-1 treated mice. Non-CM mice do not display visual memory impairments (A,B). (B) A significantly higher proportion of PbN mice passed the object recognition test when compared to PbA mice (p < 0.0001). (A) Exogenous ET-1 treatment induced cognitive dysfunction in PbN-infected mice (p < 0.05). (B) In addition, PbN ET-1 treated mice performed significantly worse than PbN saline treated mice (p < 0.0001). One-way ANOVA was performed for preference scores in A, and Chi-square was performed for success rate in B. n = 4–20/group.

Mentions: Unlike ECM mice, PbN-infected mice did not exhibit visual memory deficits at 6dpi (Fig 9A; 53.53 ± 2.9% in ECM vs. 69.07 ± 5.8% in non-CM, PbN-infected mice; P < 0.05). In addition, a greater proportion of non-CM mice were able to successfully completed the object recognition test of visual memory compared to ECM mice (Fig 9B; 86% non-CM vs. 39% ECM; P < 0.001).PbN-infected mice performed as well as uninfected controls in the object recognition test (Fig 9A; 69.07 ± 5.8% in PbN mice vs. 71.59 ± 2.7% in uninfected controls; P = NS). To establish whether the deleterious effects of ECM were in fact induced by increased production of ET-1, we treated PbN-infected mice with exogenous ET-1 and tested their visual memory. Similar to PbA-infected mice, ET-1 treated non-CM mice displayed impaired visual learning (Fig 9A; 45.22 ± 7.7% PbN+ET-1 vs. 71.59 ± 2.7% controls; P < 0.01). A significantly lower proportion of non-CM mice treated with ET-1 were able to successfully complete this memory task when compared to PbN-infected mice treated with saline (Fig 9B; 86% in PbN infected mice vs. 25% in PbN+ET-1 mice; P < 0.001), supporting our theory that cognitive impairment in ECM is induced by ET-1.


Endothelin-1 Mediates Brain Microvascular Dysfunction Leading to Long-Term Cognitive Impairment in a Model of Experimental Cerebral Malaria.

Freeman BD, Martins YC, Akide-Ndunge OB, Bruno FP, Wang H, Tanowitz HB, Spray DC, Desruisseaux MS - PLoS Pathog. (2016)

ET-1 induces cognitive dysfunction in non-CM mice.Visual memory testing was performed on PbN-infected (non-CM) and PbN-infected ET-1 treated mice. Non-CM mice do not display visual memory impairments (A,B). (B) A significantly higher proportion of PbN mice passed the object recognition test when compared to PbA mice (p < 0.0001). (A) Exogenous ET-1 treatment induced cognitive dysfunction in PbN-infected mice (p < 0.05). (B) In addition, PbN ET-1 treated mice performed significantly worse than PbN saline treated mice (p < 0.0001). One-way ANOVA was performed for preference scores in A, and Chi-square was performed for success rate in B. n = 4–20/group.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4816336&req=5

ppat.1005477.g009: ET-1 induces cognitive dysfunction in non-CM mice.Visual memory testing was performed on PbN-infected (non-CM) and PbN-infected ET-1 treated mice. Non-CM mice do not display visual memory impairments (A,B). (B) A significantly higher proportion of PbN mice passed the object recognition test when compared to PbA mice (p < 0.0001). (A) Exogenous ET-1 treatment induced cognitive dysfunction in PbN-infected mice (p < 0.05). (B) In addition, PbN ET-1 treated mice performed significantly worse than PbN saline treated mice (p < 0.0001). One-way ANOVA was performed for preference scores in A, and Chi-square was performed for success rate in B. n = 4–20/group.
Mentions: Unlike ECM mice, PbN-infected mice did not exhibit visual memory deficits at 6dpi (Fig 9A; 53.53 ± 2.9% in ECM vs. 69.07 ± 5.8% in non-CM, PbN-infected mice; P < 0.05). In addition, a greater proportion of non-CM mice were able to successfully completed the object recognition test of visual memory compared to ECM mice (Fig 9B; 86% non-CM vs. 39% ECM; P < 0.001).PbN-infected mice performed as well as uninfected controls in the object recognition test (Fig 9A; 69.07 ± 5.8% in PbN mice vs. 71.59 ± 2.7% in uninfected controls; P = NS). To establish whether the deleterious effects of ECM were in fact induced by increased production of ET-1, we treated PbN-infected mice with exogenous ET-1 and tested their visual memory. Similar to PbA-infected mice, ET-1 treated non-CM mice displayed impaired visual learning (Fig 9A; 45.22 ± 7.7% PbN+ET-1 vs. 71.59 ± 2.7% controls; P < 0.01). A significantly lower proportion of non-CM mice treated with ET-1 were able to successfully complete this memory task when compared to PbN-infected mice treated with saline (Fig 9B; 86% in PbN infected mice vs. 25% in PbN+ET-1 mice; P < 0.001), supporting our theory that cognitive impairment in ECM is induced by ET-1.

Bottom Line: Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival.ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion.This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, New York, United States of America.

ABSTRACT
Plasmodium falciparum infection causes a wide spectrum of diseases, including cerebral malaria, a potentially life-threatening encephalopathy. Vasculopathy is thought to contribute to cerebral malaria pathogenesis. The vasoactive compound endothelin-1, a key participant in many inflammatory processes, likely mediates vascular and cognitive dysfunctions in cerebral malaria. We previously demonstrated that C57BL6 mice infected with P. berghei ANKA, our fatal experimental cerebral malaria model, sustained memory loss. Herein, we demonstrate that an endothelin type A receptor (ETA) antagonist prevented experimental cerebral malaria-induced neurocognitive impairments and improved survival. ETA antagonism prevented blood-brain barrier disruption and cerebral vasoconstriction during experimental cerebral malaria, and reduced brain endothelial activation, diminishing brain microvascular congestion. Furthermore, exogenous endothelin-1 administration to P. berghei NK65-infected mice, a model generally regarded as a non-cerebral malaria negative control for P. berghei ANKA infection, led to experimental cerebral malaria-like memory deficits. Our data indicate that endothelin-1 is critical in the development of cerebrovascular and cognitive impairments with experimental cerebral malaria. This vasoactive peptide may thus serve as a potential target for adjunctive therapy in the management of cerebral malaria.

Show MeSH
Related in: MedlinePlus