Lipocalin‐2 released in response to cerebral ischaemia mediates reperfusion injury in mice

Abstract

Thrombolysis remains the only effective therapy to reverse acute ischaemic stroke. However, delayed treatment may cause serious complications including hemorrhagic transformation and reperfusion injury. The level of lipocalin-2 (LCN2) is elevated in the plasma of ischaemic stroke patients, but its role in stroke is unknown. Here, we show that LCN2 was acutely induced in mice after ischaemic stroke and is an important mediator of reperfusion injury. Increased levels of LCN2 were observed in mouse serum as early as 1 hr after transient middle cerebral artery occlusion (tMCAO), reaching peak levels at 23 hrs. LCN2 was also detected in neutrophils infiltrating into the ipsilateral hemisphere, as well as a subset of astrocytes after tMCAO, but not in neurons and microglia. Stroke injury, neurological deficits and infiltration of immune cells were markedly diminished in LCN2 null mice after tMCAO, but not after permanent MCAO (pMCAO). In vitro, recombinant LCN2 protein induced apoptosis in primary cultured neurons in a dose-dependent manner. Our results demonstrate that LCN2 is a neurotoxic factor secreted rapidly in response to cerebral ischaemia, suggesting its potential usage as an early stroke biomarker and a novel therapeutic target to reduce stroke-reperfusion injury.

cPKCγ‐mediated down‐regulation of UCHL1 alleviates ischaemic neuronal injuries by decreasing autophagy viaERK‐mTOR pathway

“…It is generally known that oxidative stress and apoptosis are involved in brain damage after cerebral ischaemia 25, 53. In this study, we found that cPKCγ gene knockout significantly enhanced OGD‐induced oxidative stress (data not shown) and apoptosis, indicating that cPKCγ may exert neuroprotective effects against oxidative stress and apoptosis during ischaemic injury.…”

“…Apoptosis and autophagy were two major morphologically distinctive forms of programmed cell death 25, 37. To explore the role of cPKCγ and UCHL1 in apoptosis and autophagy induced by MCAO or OGD treatment, the ratios of cleaved/total caspase‐3, the TUNEL staining assay and LC3‐II/total LC3 were detected.…”

“…Animals were randomly divided into three groups, namely Na€ ıve group (no treatment), Sham group (no MCAO treatment) and MCAO group (1-hr MCAO/24-hr R treatment). The MCAO-induced ischaemic stroke mouse model was performed as previous reports [24,25]. Briefly, a 5-0 surgical nylon monofilament with its tip (0.22 AE 0.01 mm in diameter) rounded by heat (#1622-A, Shadong Biotechnology Company, Beijing, China) was gently inserted into the internal carotid artery through the external carotid artery to occlude the middle cerebral artery (MCA, a point approximately 12 mm distal to the carotid bifurcation).…”

Lipocalin-2 protects the brain during inflammatory conditions

“…LCN2 has been shown to have opposing effects in EAE models of neuroinflammation(17,18), acts in a proinflammatory manner during ischemia(41), and has little impact in a model of West Nile viral encephalitis despite robust induction(19). These data suggest that the role of LCN2 in neuroinflammation may be sensitive to the inflammatory context, timing, and levels of expression.…”

Targeting of Tumor Necrosis Factor Alpha Receptors as a Therapeutic Strategy for Neurodegenerative Disorders

“…Mounting evidence recently provided insights into interesting functions of NGAL in the brain, particularly its role in neurodegenerative disorders. Robust increased NGAL protein levels were found in AD post-mortem human brain tissue [184], a mouse model for MS [186], and mouse model for cerebral ischemia [187]. Increased NGAL protein levels are detrimental to neuronal health [188] and sensitize neurons and other brain cell types to cell death upon exposure to Aβ and oxidative stress [184,189,190].…”