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

Freeman, Brandi; Martins, Yuri Chaves; Akide-Ndunge, Oscar Bate; Bruno, Fernando; Wang, Hua; Tanowitz, Herbert B.; Spray, David C.; Desruisseaux, Mahalia S.

doi:10.1371/journal.ppat.1005477

Cited by 21 publications

(20 citation statements)

References 59 publications

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“…This study had several limitations. First, as the study duration was shorter than that of other reports,12,54–56 the present findings only indicate that IGF-1 may protect from learning and memory impairment caused by sepsis. Further studies of longer duration (1 month or even longer) should be performed to evaluate the effect of IGF-1 on long-term cognition, as long-term cognitive impairment is common in patients recovering from sepsis.…”

Section: Discussioncontrasting

confidence: 67%

<p>Effects of early administration of insulin-like growth factor-1 on cognitive function in septic encephalopathy</p>

Yang¹,

Liang²,

Li³

et al. 2019

NDT

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BackgroundBoth protective and therapeutic functions of insulin-like growth factor-1 (IGF-1) in brain injury have been reported, but its effects on cognitive sequelae after septic encephalopathy (SE) remain unclear.Materials and methodsThis study was divided into three parts, and a septic model was built by cecal ligation and puncture (CLP). First, survival analysis was performed, and IGF-1’s effects on long-term cognition and depressive emotion were assessed. Second, the characteristics of IGF-1 function in cognition were evaluated. Finally, cytochrome C, caspase-9, tumor necrosis factor receptor (TNFR), and caspase-8 levels as well as cell apoptosis in the hippocampus were evaluated.ResultsIGF-1 did not reduce mortality or alleviate depressive symptoms in septic rats, but improved the memory of noxious stimulation and spatial learning and memory. These effects were observed only when IGF-1 was administered within 0–6 hours after CLP. Moreover, cytochrome C and caspase-9 expression levels were increased at 6 hours after CLP in the hippocampus, while TNFR and caspase-8 amounts were not increased until 12 hours after CLP. Cell apoptosis increased at 12 hours after CLP, but was inhibited by IGF-1.ConclusionCognitive impairment in rats recovering from SE is associated with cell apoptosis in the hippocampus. Supplementation of IGF-1 reduces cell apoptosis by preventing the over-expression of cytochrome C and TNFR, and results in improved cognitive function. However, improvement only occurs when IGF-1 is administered at the early stage (within 6 hours) of sepsis. As cytochrome C activation occurs earlier than that of TNFR in this study, cytochrome C may be the main factor inducing apoptosis in early SE.

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Section: Discussioncontrasting

confidence: 67%

<p>Effects of early administration of insulin-like growth factor-1 on cognitive function in septic encephalopathy</p>

Yang¹,

Liang²,

Li³

et al. 2019

NDT

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“…In a recent publication, we demonstrated that treatment of PbA-infected mice with endothelin receptor A blockers preserved vascular integrity, prevented leukocyte infiltration, greatly mitigated long-term memory loss, and subsequently improved survival in mice with ECM. 75 Microvascular alterations are a hallmark of CM, yet there are currently no therapeutic strategies targeting these vascular complications in clinical settings. This study suggests that exploration of therapeutics aimed at targeting the ET-1 signaling cascade is warranted, as they may prevent both vascular and cognitive deficits in patients with CM.…”

Section: Et-1 Induces Murine Cerebral Malariamentioning

confidence: 99%

Endothelin-1 Treatment Induces an Experimental Cerebral Malaria–Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65

Martins

Freeman

Ndunge

et al. 2016

The American Journal of Pathology

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Plasmodium berghei ANKA infection of C57BL/6 mice is a widely used model of experimental cerebral malaria (ECM). By contrast, the nonneurotropic P. berghei NK65 (PbN) causes severe malarial disease in C57BL/6 mice but does not cause ECM. Previous studies suggest that endothelin-1 (ET-1) contributes to the pathogenesis of ECM. In this study, we characterize the role of ET-1 on ECM vascular dysfunction. Mice infected with 10 6 PbN-parasitized red blood cells were treated with either ET-1 or saline from 2 to 8 days postinfection (dpi). Plasmodium berghei ANKAeinfected mice served as the positive control. ET-1e treated PbN-infected mice exhibited neurological signs, hypothermia, and behavioral alterations characteristic of ECM, dying 4 to 8 dpi. Parasitemia was not affected by ET-1 treatment. Saline-treated PbNinfected mice did not display ECM, surviving until 12 dpi. ET-1etreated PbN-infected mice displayed leukocyte adhesion to the vascular endothelia and petechial hemorrhages throughout the brain at 6 dpi. Intravital microscopic images demonstrated significant brain arteriolar vessel constriction, decreased functional capillary density, and increased blood-brain barrier permeability. These alterations were not present in either ET-1etreated uninfected or saline-treated PbN-infected mice. In summary, ET-1 treatment of PbN-infected mice induced an ECM-like syndrome, causing brain vasoconstriction, adherence of activated leukocytes in the cerebral microvasculature, and blood-brain barrier leakage, indicating that ET-1 is involved in the genesis of brain microvascular alterations that are the hallmark of ECM. (Am J Pathol 2016 http://dx

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“…Endothelin family peptide ET-1 (Pre-proendothelin) also plays an important role in inducing BBB damage and produces a CM-like picture in rodent models [ 113 ]. Selective endothelin receptor antagonists also improved outcome in cognitive decline and decreased brain hemorrhages in mice [ 113 – 115 ].…”

Section: Introductionmentioning

confidence: 99%

Pathophysiology and neurologic sequelae of cerebral malaria

Schiess¹,

Villabona-Rueda

Cottier

et al. 2020

Malar J

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Cerebral malaria (CM), results from Plasmodium falciparum infection, and has a high mortality rate. CM survivors can retain lifelong post CM sequelae, including seizures and neurocognitive deficits profoundly affecting their quality of life. As the Plasmodium parasite does not enter the brain, but resides inside erythrocytes and are confined to the lumen of the brain's vasculature, the neuropathogenesis leading to these neurologic sequelae is unclear and underinvestigated. Interestingly, postmortem CM pathology differs in brain regions, such as the appearance of haemorragic punctae in white versus gray matter. Various host and parasite factors contribute to the risk of CM, including exposure at a young age, parasite-and host-related genetics, parasite sequestration and the extent of host inflammatory responses. Thus far, several proposed adjunctive treatments have not been successful in the treatment of CM but are highly needed. The region-specific CM neuro-pathogenesis leading to neurologic sequelae is intriguing, but not sufficiently addressed in research. More attention to this may lead to the development of effective adjunctive treatments to address CM neurologic sequelae.

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

Cited by 21 publications

References 59 publications

<p>Effects of early administration of insulin-like growth factor-1 on cognitive function in septic encephalopathy</p>

<p>Effects of early administration of insulin-like growth factor-1 on cognitive function in septic encephalopathy</p>

Endothelin-1 Treatment Induces an Experimental Cerebral Malaria–Like Syndrome in C57BL/6 Mice Infected with Plasmodium berghei NK65

Pathophysiology and neurologic sequelae of cerebral malaria

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