Histological and cognitive alterations in adult diabetic rats following an episode of juvenile diabetic ketoacidosis: Evidence of permanent cerebral injury

Glaser, Nicole; Russell, Jennifer Sasaki; Cohen, Michael X; Little, Christopher; O’Donnell, Martha E; Sall, Jeffrey W.

doi:10.1016/j.neulet.2017.04.035

Cited by 9 publications

(6 citation statements)

References 24 publications

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“…[1][2][3][4] Recent studies have linked DKA to declines in cognition in children with T1D, demonstrating associations between DKA and reductions in IQ and memory function, as well as structural alterations in the brain. [5][6][7][8][9][10] In previous work by our group using a juvenile rat model, we found that DKA causes a neuroinflammatory response with reactive astrogliosis and activation of microglia, [11][12][13] along with increased levels of inflammatory mediators (cytokines, chemokines and matrix metalloproteinases (MMPs)) in brain tissue lysates. 14 Notably, we found evidence that neuroinflammation persists into adulthood in rats exposed to DKA as juveniles, 14 suggesting that DKA might trigger chronic low-level neuroinflammation.…”

Section: Introductionmentioning

confidence: 94%

Effects of TRAM-34 and minocycline on neuroinflammation caused by diabetic ketoacidosis in a rat model

Glaser

Chu

Weiner

et al. 2022

BMJ Open Diab Res Care

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IntroductionDiabetic ketoacidosis (DKA) causes acute and chronic neuroinflammation that may contribute to cognitive decline in patients with type 1 diabetes. We evaluated the effects of agents that reduce neuroinflammation (triarylmethane-34 (TRAM-34) and minocycline) during and after DKA in a rat model.Research design and methodsJuvenile rats with DKA were treated with insulin and saline, either alone or in combination with TRAM-34 (40 mg/kg intraperitoneally twice daily for 3 days, then daily for 4 days) or minocycline (45 mg/kg intraperitoneally daily for 7 days). We compared cytokine and chemokine concentrations in brain tissue lysates during DKA among the three treatment groups and in normal controls and diabetic controls (n=9–15/group). We also compared brain inflammatory mediator levels in these same groups in adult diabetic rats that were treated for DKA as juveniles.ResultsBrain tissue concentrations of chemokine (C-C) motif ligand (CCL)3, CCL5 and interferon (IFNγ) were increased during acute DKA, as were brain cytokine composite scores. Both treatments reduced brain inflammatory mediator levels during acute DKA. TRAM-34 predominantly reduced chemokine concentrations (chemokine (C-X-C) motif ligand (CXCL-1), CCL5) whereas minocycline had broader effects, (reducing CXCL-1, tumor necrosis factor (TNFα), IFNγ, interleukin (IL) 2, IL-10 and IL-17A). Brain inflammatory mediator levels were elevated in adult rats that had DKA as juveniles, compared with adult diabetic rats without previous DKA, however, neither TRAM-34 nor minocycline treatment reduced these levels.ConclusionsThese data demonstrate that both TRAM-34 and minocycline reduce acute neuroinflammation during DKA, however, treatment with these agents for 1 week after DKA does not reduce long-term neuroinflammation.

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Section: Introductionmentioning

confidence: 94%

Effects of TRAM-34 and minocycline on neuroinflammation caused by diabetic ketoacidosis in a rat model

Glaser

Chu

Weiner

et al. 2022

BMJ Open Diab Res Care

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“…Механизмы повреждения головного мозга при ДКА с последующим формированием когнитивных нарушений до конца не изучены и на сегодняшний день остаются областью активных исследований [19,29]. Экспериментальные исследования на живот-ных и клинические исследования в педиатрической популяции показали, что ДКА может приводить к повреждению нейронов и астроцитов на фоне нейровоспаления [30,31], процессов апоптоза [32,33], нарушения процессов подавления пролиферации нейрональных клеток (нейрогенеза) [34,35] и нейродегенерации [36].…”

Section: патофизиологические механизмы формирования когнитивных наруш...unclassified

“…Острая гипергликемия на фоне ДКА может привести к усилению оксидативного стресса, что также может спровоцировать когнитивный дефицит у детей и подростков с СД 1-го типа [37][38][39]. Существующие данные свидетельствуют о том, что патофизиологические изменения, происходящие во время ДКА, негативно влияют на головной мозг, вызывая в первую очередь воспалительную реакцию и вазогенный отек, что может служить триггерами к возникновению когнитивной дисфункции [29]. Исследования на животных показали, что ДКА вызывает реактивный астроглиоз и активацию микроглии в головном мозге, и эти изменения наиболее заметны в течение первых 24 ч после начала ДКА, хотя некоторые воспалительные изменения сохраняются и через 72 ч после возникновения ДКА [29].…”

Section: патофизиологические механизмы формирования когнитивных наруш...unclassified

“…Существующие данные свидетельствуют о том, что патофизиологические изменения, происходящие во время ДКА, негативно влияют на головной мозг, вызывая в первую очередь воспалительную реакцию и вазогенный отек, что может служить триггерами к возникновению когнитивной дисфункции [29]. Исследования на животных показали, что ДКА вызывает реактивный астроглиоз и активацию микроглии в головном мозге, и эти изменения наиболее заметны в течение первых 24 ч после начала ДКА, хотя некоторые воспалительные изменения сохраняются и через 72 ч после возникновения ДКА [29]. Данные стойкие воспалительные нарушения предполагают процессы продолжающегося повреждения головного мозга уже после окончания ДКА [29].…”

Section: патофизиологические механизмы формирования когнитивных наруш...unclassified

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Diabetic ketoacidosis and cognitive impairment in children and adolescents

Magomedova,

Bykov,

Baturin

2023

Bûll. sib. med.

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The aim of the literature review was to highlight modern scientific sources on the formation and clinical manifestations of cognitive impairment in children and adolescents with type 1 diabetes mellitus (DM) after diabetic ketoacidosis (DKA). Type 1 DM is one of the most prevalent endocrine disorders in childhood and adolescence. DKA is the most common acute complication of type 1 DM that may cause cognitive impairment. Cerebral edema is the main cause of cerebral vascular insufficiency in patients with DKA. However, the mechanisms underlying the development of cognitive dysfunction in DKA have not been fully elucidated.The leading hypotheses include development of neuroinflammation, oxidative stress, disruption of neurogenesis, and neurodegeneration. Hypoxic – ischemic injury and changes in the brain neuroanatomy may also cause cognitive dysfunction. Disruption of some brain structures has been reported after DKA episodes, primarily affecting the white matter. Clinical studies in the pediatric population support the presence of a correlation between the severity and frequency of DKA and the severity of cognitive impairment. Cognitive dysfunction in children and adolescents after a DKA episode can manifest through decreased attention, impaired memory and executive function, and reduced IQ. The earliest possible diagnosis of cognitive impairment in pediatric patients with symptoms of DKA in the context of type 1 DM can improve the treatment prognosis for this endocrinopathy.

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“…DKA is also reported to increase the risk for Alzheimer's disease (AD) in patients with type 2 diabetes mellitus (T2DM) [7]. It has been demonstrated in diabetic rats that DKA can induce deficits in learning and memory associated with astrogliosis [8,9]. There is increasing evidence to support that DM is associated with neurological disorders.…”

Section: Introductionmentioning

confidence: 99%

Diabetic Ketoacidosis Induces Tau Hyperphosphorylation in Rat Brain

Basurto-Islas,

Tung,

Dai

et al. 2024

Journal of Alzheimer's Disease Reports

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Background: Diabetes mellitus (DM) increases the risk for cognitive impairment and Alzheimer’s disease (AD). Diabetic ketoacidosis (DKA), a serious complication of DM, may also cause brain damage and further AD, but the underlying molecular mechanisms remain unclear. Objective: Our objective was to understand how DKA can promote neurodegeneration in AD. Methods: We induced DKA in rats through intraperitoneal injection of streptozotocin, followed by starvation for 48 hours and investigated AD-related brain alterations focusing on tau phosphorylation. Results: We found that DKA induced hyperphosphorylation of tau protein at multiple sites associated with AD. Studies of tau kinases and phosphatases suggest that the DKA-induced hyperphosphorylation of tau was mainly mediated through activation of c-Jun N-terminal kinase and downregulation of protein phosphatase 2A. Disruption of the mTOR-AKT (the mechanistic target of rapamycin−protein kinase B) signaling pathway and increased levels of synaptic proteins were also observed in the brains of rats with DKA. Conclusions: These results shed some light on the mechanisms by which DKA may increase the risk for AD.

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Histological and cognitive alterations in adult diabetic rats following an episode of juvenile diabetic ketoacidosis: Evidence of permanent cerebral injury

Cited by 9 publications

References 24 publications

Effects of TRAM-34 and minocycline on neuroinflammation caused by diabetic ketoacidosis in a rat model

Effects of TRAM-34 and minocycline on neuroinflammation caused by diabetic ketoacidosis in a rat model

Diabetic ketoacidosis and cognitive impairment in children and adolescents

Diabetic Ketoacidosis Induces Tau Hyperphosphorylation in Rat Brain

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