Effects of cathepsins B and L inhibition on postischemic protein alterations in the brain

Anagli, John; Abounit, Kadija; Stemmer, Paul M.; Han, Yu; Allred, Lisa; Weinsheimer, Shantel; Movsisyan, A.B.; Seyfried, Donald

doi:10.1016/j.bbrc.2007.11.104

Cited by 26 publications

(20 citation statements)

References 34 publications

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“…However, inhibitors of cathepsin B (and L) have been shown to have a neuroprotective effect in animal models of ischemia, preventing apoptosis [48; 49; 50; 51; 52] and prolonged treatment of animals with cathepsin inhibitors do not produce any significant neurological toxic effects [19; 20]. The deleterious effects of protease loss in the cathepsin B and L double knockout mice are primarily due to early post-natal effects on rapidly proliferating neuronal cells whereas non-proliferating cells of the central nervous system of adult mice appears to be refractory to protease inhibition.…”

Section: Discussionmentioning

confidence: 99%

Induction of cell death in neuroblastoma by inhibition of cathepsins B and L

Colella

Glazewski

et al. 2010

Cancer Letters

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A specific irreversible inhibitor of both cathepsins B and L, Fmoc-Tyr-Ala-CHN2 (FYAD) induced apoptosis of neuroblastoma cells but not other tumor cells. Cysteine protease inhibitors that were not efficient inhibitors of both proteases did not cause death of any cell line tested. Apoptosis was preceded by accumulation of large electron dense vesicles and multivesicular bodies in the cytoplasm. Exposure of cells to the cathepsin D inhibitor, pepstatin, failed to rescue cells from FYAD-induced death. These results indicate that inhibition of cathepsins B and L may provide a unique mechanism for selectively inducing death of neuroblastoma with limited toxicity to normal cells and tissues.

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Section: Discussionmentioning

confidence: 99%

Induction of cell death in neuroblastoma by inhibition of cathepsins B and L

Colella

Glazewski

et al. 2010

Cancer Letters

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“…Treatment with cathepsin B inhibitors, including stefin A, epoxysuccinyl peptides and cysteine protease inhibitor 1, reduced ischemia-induced neuron death. [27][28][29][30] However, in other pathological conditions, autophagy is reported to be associated with neuroprotection. [31][32][33] Thus, the role of autophagy in cell death and survival in cerebral ischemia remains to be defined.…”

Section: Discussionmentioning

confidence: 99%

Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways

Wen¹,

Sheng²,

Zhang³

et al. 2008

Autophagy

366

296

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It has been reported that ischemic insult increases the formation of autophagosomes and activates autophagy. However, the role of autophagy in ischemic neuronal damage remains elusive. This study was taken to assess the role of autophagy in ischemic brain damage. Focal cerebral ischemia was introduced by permanent middle cerebral artery occlusion (pMCAO). Activation of autophagy was assessed by morphological and biochemical examinations. To determine the contribution of autophagy/lysosome to ischemic neuronal death, rats were pretreated with a single intracerebral ventricle injection of the autophagy inhibitors 3-methyl-adenine (3-MA) and bafliomycin A1 (BFA) or the cathepsin B inhibitor Z-FA-fmk after pMCAO. The effects of 3-MA and Z-FA-fmk on brain damage, expression of proteins involved in regulation of autophagy and apoptosis were assessed with 2,3,5-triphenyltetrazolium chloride (TTC) staining and immunoblotting. The results showed that pMACO increased the formation of autophagosomes and autolysosomes, the mRNA and protein levels of LC3-II and the protein levels of cathepsin B. 3-MA, BFA and Z-FA-fmk significantly reduced infarct volume, brain edema and motor deficits. The neuroprotective effects of 3-MA and Z-FA-fmk were associated with an inhibition on ischemia-induced upregulation of LC3-II and cathepsin B and a partial reversion of ischemia-induced downregulation of cytoprotective Bcl-2. These results demonstrate that ischemic insult activates autophagy and an autophagic mechanism may contribute to ischemic neuronal injury. Thus, autophagy may be a potential target for developing a novel therapy for stroke.

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“…35 In addition, Seyfried et al have shown that neuronal cathepsin B undergoes increased expression and activation within 2 hours of reperfusion after a 2-hour MCA occlusion and may be a mechanism contributing to neuronal cell death and that intraventricular infusion of stefin A, an inhibitor of cathepsin B, significantly reduces cerebral infarct volume in rats. Recently, Angali et al, 2 have demonstrated that a posttreatment with cysteine protease inhibitor (CP-1) reduced infract volume, neurological deficits and cathepsin B activity in a rat model of focal ischemia.…”

Section: Participation Of Lysosomal Proteases In Neuron Death After Gmentioning

confidence: 99%

Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin?

Rami

Kögel²

2008

Autophagy

122

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Autophagy is a homeostatic cellular process required for the recycling of proteins and damaged organelles, and in most scenarios is believed to promote cell survival. However, there is accumulating evidence that under certain pathological situations, autophagy can also trigger and mediate programmed cell death (type II death). Despite the well-established pathophysiological role of apoptosis (type I cell death) in post-ischemic neuron death, there is now increasing interest whether alternative types of programmed cell death might be involved in regulation of neuronal death after both global and focal cerebral ischemia. Initial studies demonstrating the involvement of lysosomal proteases of the cathepsin family in neuron death after global ischemia already had suggested that this type of cell death may occur in an autophagy-dependent manner. Recently it was also shown that focal ischemia is associated with potently enhanced expression of the autophagy regulator Beclin 1 and subcellular redistribution of the autophagic marker LC3 to vacuolic structures in ischemic neurons. Increasing evidence suggests that the effects of autophagy are highly contextual. An insufficient autophagic response might render cells more susceptible to stress conditions whereas on the other hand prolonged overactivation of autophagy can lead to a complete self digestion of the cell. The extent of autophagy may represent a master switch between cell survival and cell death, and it will be of fundamental importance to dissect whether autophagy is primarily a strategy for survival or whether autophagy can also be a part of a cell death program and thus contribute to cell death after cerebral ischemia. A profound understanding of the biological effects and the mechanisms underlying ischemia-induced autophagy in neurons might be helpful in seeking effective new treatments for cerebral ischemia.

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Effects of cathepsins B and L inhibition on postischemic protein alterations in the brain

Cited by 26 publications

References 34 publications

Induction of cell death in neuroblastoma by inhibition of cathepsins B and L

Induction of cell death in neuroblastoma by inhibition of cathepsins B and L

Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways

Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin?

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