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

Abstract

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.

The Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Oral Cavity and Abdominal Organs

“…Diabetes is a multisystem disease, and advanced, untreated diabetes may lead to diabetic ketoacidosis and thus neuroinflammation. Although a study on rats has not shown elevated brain concentrations of the rat equivalent of CXCL1 during diabetic ketoacidosis [90], the link between diabetes, neuroinflammation and CXCL1 needs to be investigated in a human model.…”

Metabolic disorders on cognitive dysfunction after traumatic brain injury

“…The administration of mitochondrial uncouplers to mice with TBI significantly restored cognitive function by reducing oxidative stress and hippocampal cell death [7]. Inflammation Cytokines are elevated in the plasma of diabetic patients, thereby activating microglia, causing central inflammation, and accelerating cognitive dysfunction [16,17] Ferroptosis Downregulation of SLC40A1 leads to ferroptosis in the brain and subsequent cognitive dysfunction in diabetes [18] DKA CBF Cerebral edema is associated with regional CBF abnormalities in children with DKA [21] Inflammation DKA induces acute systemic inflammation and chronic neuroinflammation [22] High cholesterol Inflammation and BBB dysfunction HCD induces severe astrogliosis and decreases tight junction protein expression [23] Inflammation and cerebral microcirculation HCD induces cerebral vasodilator dysfunction and upregulates galectin-3 immunoreactivity in microglia [24] Inflammation and abnormal protein deposition HCD activates microglia and accelerates Aβ accumulation and tau phosphorylation [25] a Abbreviations: BDNF, brain-derived neurotrophic factor; BMVECs, brain microvascular endothelial cells; HCD, high-cholesterol diet; ICAM, intercellular cell adhesion molecule; PDGF-Rβ, platelet-derived growth factor receptor beta; SLC40A1, solute carrier family 40 member 1; VCAM, vascular cell adhesion molecule.…”

“…Cognitive impairment is closely related to the severity of DKA [20]. Although the mechanism by which DKA induces cognitive impairment is unclear, it may be caused by altered cerebral blood flow (CBF) [21] and neuroinflammatory responses [22] (Table 1). Although DKA has been demonstrated to play an important role in cognitive function in children, there are few studies on the relationship between DKA and cognitive impairment.…”

Corresponding risk factors between cognitive impairment and type 1 diabetes mellitus: A narrative review

“…In the original study by Glaser of rat models, DKA caused acute systemic inflammation, including neuroinflammation. Importantly, the neuroinflammatory response induced by DKA was long-lasting, suggesting that DKA may contribute to long-term cognitive decline in patients with diabetes [62]. Although the underlying mechanisms remained to be elucidated, as a serious complication of hyperglycemia, it was suggested that DKA played an important in diabetes-related cognitive decline.…”