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

Objective: FK866 is an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), which exhibits neuroprotective effects in ischemic brain injury. However, in traumatic brain injury (TBI), the role and mechanism of FK866 remain unclear. The present research was aimed to investigate whether FK866 could attenuate TBI and clarified the underlying mechanisms. Methods: A controlled cortical impact model was established, and FK866 at a dose of 5 mg/kg was administered intraperitoneally at 1 h and 6 h, then twice per day post-TBI until sacrifice. Brain water content, Evans blue dye extravasation, modified neurological severity scores (mNSS), Morris water maze test, enzyme-linked immunosorbent assay (ELISA), immunofluorescence staining, and western blot were performed. Results: The results demonstrated that FK866 significantly mitigated the brain edema, blood-brain barrier (BBB) disruption, and ameliorated the neurological function post-TBI. Moreover, FK866 decreased the number of Iba-1-positive cells, GFAP-positive astrocytes, and AQP4-positive cells. FK866 reduced the protein levels of proinflammatory cytokines and inhibited NF-jB from translocation to the nucleus. FK866 upregulated the expression of Bcl-2, diminished the expression of Bax and caspase 3, and the number of apoptotic cells. Moreover, p38 MAPK and ERK activation were significantly inhibited by FK866. Interpretation: FK866 attenuated TBI-induced neuroinflammation and apoptosis, at least in part, through p38/ERK MAPKs signaling pathway. 742

show abstract

“…Morris water maze test was conducted as previously described 18 . Briefly, the rat was trained to find the platform before TBI or sham operation.…”

Section: Methodsmentioning

confidence: 99%

Neuroprotective effects of FK866 against traumatic brain injury: Involvement of p38/ERK pathway

Tan

Chen

Ren

et al. 2020

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…Of note, melatonin has been suggested to inhibit autophagy in other settings 73 . Moreover, post-injury chloroquine administration limited neuronal damage and improved neurological recovery in rats that were subjected to controlled cortical impact 104 , as did 3-MA and BafA1 administered as a prophylactic intervention in a mouse weight-drop model 105 . Thus, autophagy activators may be beneficial for patients experiencing SCI or SAH, even if administered in a therapeutic (as opposed to prophylactic) setting.…”

Section: Autophagy As a Therapeutic Targetmentioning

confidence: 98%

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Galluzzi

Pedro

Levine

et al. 2017

Nat Rev Drug Discov

716

589

View full text Add to dashboard Cite

Autophagy is central to the maintenance of organismal homeostasis in both physiological and pathological situations. Accordingly, alterations in autophagy have been linked to clinically relevant conditions as diverse as cancer, neurodegeneration and cardiac disorders. Throughout the past decade, autophagy has attracted considerable attention as a target for the development of novel therapeutics. However, such efforts have not yet generated clinically viable interventions. In this Review, we discuss the therapeutic potential of autophagy modulators, analyse the obstacles that have limited their development and propose strategies that may unlock the full therapeutic potential of autophagy modulation in the clinic.

show abstract

“…Coronal sections (10 µm) were obtained from the anterior area of the left hemisphere. Immunofluorescence was performed as described previously (15). Briefly, brain tissue samples were fixed in 4% paraformaldehyde (Bio-Rad Laboratories, Inc.) for 24 h, then transferred to a 30% sucrose solution containing 0.1 mol/l phosphate-buffered saline (PBS; pH 7.4).…”

Section: Models Of Tbimentioning

confidence: 99%

“…Western blot analysis was performed as previously described (15). Briefly, rats were anesthetized and underwent intracardiac perfusion with 0.1 mol/l PBS (pH 7.4).…”

Section: Western Blot Analysismentioning

confidence: 99%

See 1 more Smart Citation

Hsp70 inducer, 17-allylamino-demethoxygeldanamycin, provides neuroprotection via anti-inflammatory effects in a rat model of traumatic brain injury

Wang

Zhou

et al. 2016

Experimental and Therapeutic Medicine

View full text Add to dashboard Cite

Abstract. Traumatic brain injury (TBI) is the predominant cause of mortality in young adults and children living in China. TBI induces inflammatory responses; in addition, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 are important pro-inflammatory cytokines. Considering the observation that Hsp-70 overexpression can exert neuroprotection, identifying a drug that is able to induce the upregulation of Hsp70 has the potential to be a promising therapy for the treatment of neurological diseases. Thus, the present study assessed the clinical effectiveness of an anticancer drug and Hsp70 activator, 17-allylamino-demethoxygeldanamycin (17-AAG), to evaluate its potential as a treatment for patients with TBI. The aim of present study was to determine the neuroprotective effects of 17-AAG following trauma and to investigate the underlying mechanisms of action. To establish rat models, rats were subjected to a controlled cortical impact injury and randomly divided into vehicle or 17-AAG groups. In the 17-AAG group, rats were administered with an intraperitoneal injection of 17-AAG (80 mg/kg) immediately following the establishment of TBI. The motor function was measured using Neurologic Severity Score, and neuronal death was evaluated using immunofluorescence. The expression levels of GLT-1, Bcl-2 and Hsp-70 were detected by western blot analysis and the expression levels of inflammatory cytokines were quantified using ELISA. The present study determined that 17-AAG significantly reduced brain edema and motor neurological deficits (P<0.05), in addition to increasing neuronal survival. The aforementioned findings are associated with a downregulation of the expression levels of pro-inflammatory cytokines TNF-α, IL-1β and IL-6. Conversely, no significant changes of glutamate transporter-1 expression were observed. The present results suggest that 17-AAG treatment may provide a neuroprotective effect by reducing inflammation following TBI. IntroductionTraumatic brain injury (TBI) is the leading cause of mortality in young adults and children living in China (1). Head trauma has numerous consequences in the brain, including axonal damage, microvascular alterations and blood-brain barrier disruption (2). The aforementioned outcomes are a result of both primary and secondary mechanisms following injury (3). Primary damage is a result of mechanical factors occurring immediately following trauma. Conversely, the fundamental mechanisms underlying secondary damage in TBI include inflammation, oxygen free radicals, brain edema formation and neuronal apoptosis (4). In particular, previous studies have demonstrated that tumor necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 are crucial pro-inflammatory cytokines following trauma (5-7). Although the potential effects of TNF-α, IL-1β and IL-6 in human patients with TBI have yet to be elucidated, evidence from animal models has revealed that upregulated expression levels of the aforementioned cytokines are harmful, whereas their attenuation may alleviate tissue ...

show abstract

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

Cited by 44 publications

References 31 publications

Neuroprotective effects of FK866 against traumatic brain injury: Involvement of p38/ERK pathway

Neuroprotective effects of FK866 against traumatic brain injury: Involvement of p38/ERK pathway

Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles

Hsp70 inducer, 17-allylamino-demethoxygeldanamycin, provides neuroprotection via anti-inflammatory effects in a rat model of traumatic brain injury

Contact Info

Product

Resources

About