Autophagy is Increased after Traumatic Brain Injury in Mice and is Partially Inhibited by the Antioxidant γ-glutamylcysteinyl Ethyl Ester

Lai, Yi‐Chen; Rw, Hickey; Chen, Y; Bayır, Hülya; Ml, Sullivan; Chu, Charleen T.; Kochanek, Patrick M.; Ce, Dixon; Lw, Jenkins; Sh, Graham; Watkins, Simon C.; Rs, Clark

doi:10.1038/sj.jcbfm.9600551

Cited by 160 publications

(123 citation statements)

References 35 publications

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“…39,40 In animal models, pretreatment with antioxidants such as vitamin E and ␥-glutamylcysteinyl ethyl ester protect against neuronal injury and is accompanied by downregulation of autophagy. 41,42 Overexpression of HO-1 in lung epithelial cells downregulated both ROS generation and autophagy during cigarette smoke extract-induced injury. 43 Similarly, we demonstrate that overexpression of HO-1 in kidney epithelial cells significantly reduced ROS generation compared with that in control cells after cisplatin treatment, while delaying the onset of autophagy induction and conferring protection.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury

Bolisetty

Traylor²,

Kim³

et al. 2010

Journal of the American Society of Nephrology

143

125

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Autophagy is a tightly regulated, programmed mechanism to eliminate damaged organelles and proteins from a cell to maintain homeostasis. Cisplatin, a chemotherapeutic agent, accumulates in the proximal tubules of the kidney and causes dose-dependent nephrotoxicity, which may involve autophagy. In the kidney, cisplatin induces the protective antioxidant heme oxygenase-1 (HO-1). In this study, we examined the relationship between autophagy and HO-1 during cisplatin-mediated acute kidney injury (AKI). In wild-type primary proximal tubule cells (PTC), we observed a time-dependent increase in autophagy after cisplatin. In HO-1 Ϫ/Ϫ PTC, however, we observed significantly higher levels of basal autophagy, impaired progression of autophagy, and increased apoptosis after cisplatin. Restoring HO-1 expression in these cells reversed the autophagic response and inhibited apoptosis after treatment with cisplatin. In vivo, although both wild-type and HO-1-deficient mice exhibited autophagosomes in the proximal tubules of the kidney in response to cisplatin, HO-1-deficient mice had significantly more autophagosomes, even in saline-treated animals. In addition, ecdysone-induced overexpression of HO-1 in cells led to a delay in autophagy progression, generated significantly lower levels of reactive oxygen species, and protected against cisplatin cytotoxicity. These findings demonstrsate that HO-1 inhibits autophagy, suggesting that the heme oxygenase system may contain therapeutic targets for AKI.

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Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury

Bolisetty

Traylor²,

Kim³

et al. 2010

Journal of the American Society of Nephrology

143

125

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“…Identification of autophagosomes remains the 'gold standard' method for the detection of autophagy (7). The first direct evidence that autophagy is increased following TBI, was reported in a study by Lai et al, which used a controlled cortical impact model of TBI to investigate this effect (8). More recently, a study administered a selective inhibitor of autophagy, 3-methyladenine, in a rat model of transient focal cerebral ischemia.…”

Section: Introductionmentioning

confidence: 99%

Chloroquine exerts neuroprotection following traumatic brain injury via suppression of inflammation and neuronal autophagic death

Cui

Gao

Cui

et al. 2015

Molecular Medicine Reports

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Abstract. The antimalarial drug, chloroquine (CQ), has been reported as an autophagy inhibitor in a variety of disorders, including Alzheimer's disease and brain ischemia. To the best of our knowledge, no studies to date have examined the potential for CQ to provide neuroprotection in animal models of traumatic brain injury (TBI). The aim of this study was to investigate the neuroprotective actions of CQ in TBI and to determine the mechanisms underlying this effect. Rats were immediately subjected to a diffuse cortical impact injury caused by a modified weight-drop device and divided randomly into three groups: sham-operated, CQ treatment and vehicle. The CQ treatment group was administered CQ (intraperitoneally, 3 mg/kg body weight) immediately following the induction of injury. The co-localization of neuron-specific nuclear protein (NeuN) and microtubule-associated protein 1 light chain 3 (LC3), was followed by immunofluorescent staining. The expression of LC3 and inflammatory cytokines was identified by western blot analysis. Wet-dry weight method was utilized to evaluate TBI-induced brain edema. Motor function was evaluated using the Neurological Severity Score (NSS) scale and the Morris water maze was employed to assess spatial learning ability. This study demonstrated that the administration of CQ attenuates TBI-induced cerebral edema, and the associated motor and cognitive functional deficits that occur post-injury. Following the induction of cerebral trauma, CQ treatment significantly suppressed neuronal autophagy and reduced expression levels of the inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), in the rat hippocampus. Our results have provided in vivo evidence that CQ may exert neuroprotective effects following TBI, in attenuating brain edema and improving neurological functioning, by reducing the damaging consequences of neuronal autophagy and cerebral inflammation.

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“…36,37 ABCB1 (also known as MDR1 or P-glycoprotein) has been studied more so than ABCC1. ABCB1 is a prominent component of the dynamic BBB, with substrates relevant to the management of TBI that include opioids (e.g., morphine, fentanyl), anti-epileptics (e.g., phenytoin), and antibiotics (e.g., vancomycin).…”

Section: Abcc1 and Abcb1 In Human Brain After Severe Tbimentioning

confidence: 99%

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

Willyerd

Empey

Philbrick

et al. 2016

Journal of Neurotrauma

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Adenosine triphosphate-binding cassette (ABC) transport proteins ABCC1 and ABCB1 (also known as multidrug resistance-associated protein 1 and p-glycoprotein, respectively), are key membrane efflux transporters of drugs and endogenous substrates, including in the brain. The impact of traumatic brain injury (TBI) on ABCC1 and ABCB1 expression in humans is unknown. We hypothesized that ABCC1 and ABCB1 expression would be altered in brain tissue from patients acutely after severe TBI. Archived TBI samples (n = 10) from our Brain Trauma Research Center and control samples (n = 7) from our Alzheimer Disease Research Center were obtained under Institutional Review Board approval. Protein was extracted from fresh frozen cortical brain tissue for Western blot analysis and sections were obtained from fixed cortical tissue for immunohistochemistry. Relative abundance of ABCC1 was increased in samples from TBI versus controls (2.8 -2.5 fold; p = 0.005). ABCC1 immunohistochemistry was consistent with Western blot data, with increased immunoreactivity in cerebral blood vessel walls, as well as cells with the morphological appearance of neurons and glia in TBI versus controls. Relative abundance of ABCB1 was similar between TBI and controls ( p = 0.76), and ABCB1 immunoreactivity was primarily associated with cerebral blood vessels in both groups. These human data show that TBI increases ABCC1 expression in the brain, consistent with possible implications for both patients receiving pharmacological inhibitors and/or substrates of ABCC1 after TBI.

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Autophagy is Increased after Traumatic Brain Injury in Mice and is Partially Inhibited by the Antioxidant γ-glutamylcysteinyl Ethyl Ester

Cited by 160 publications

References 35 publications

Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury

Heme Oxygenase-1 Inhibits Renal Tubular Macroautophagy in Acute Kidney Injury

Chloroquine exerts neuroprotection following traumatic brain injury via suppression of inflammation and neuronal autophagic death

Expression of ATP-Binding Cassette Transporters B1 and C1 after Severe Traumatic Brain Injury in Humans

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