Prokineticin 2 is an endangering mediator of cerebral ischemic injury

Abstract

Stroke causes brain dysfunction and neuron death, and the lack of effective therapies heightens the need for new therapeutic targets. Here we identify prokineticin 2 (PK2) as a mediator for cerebral ischemic injury. PK2 is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Multiple biological roles for PK2 have been discovered, including circadian rhythms, angiogenesis, and neurogenesis. However, the role of PK2 in neuropathology is unknown. Using primary cortical cultures, we found that PK2 mRNA is up-regulated by several pathological stressors, including hypoxia, reactive oxygen species, and excitotoxic glutamate. Glutamate-induced PK2 expression is dependent on NMDA receptor activation and extracellular calcium. Enriched neuronal culture studies revealed that neurons are the principal source of glutamate-induced PK2. Using in vivo models of stroke, we found that PK2 mRNA is induced in the ischemic cortex and striatum. Central delivery of PK2 worsens infarct volume, whereas PK2 receptor antagonist decreases infarct volume and central inflammation while improving functional outcome. Direct central inhibition of PK2 using RNAi also reduces infarct volume. These findings indicate that PK2 can be activated by pathological stimuli such as hypoxia-ischemia and excitotoxic glutamate and identify PK2 as a deleterious mediator for cerebral ischemia.excitotoxicity | RNA interference | Akt | Erk1,2 | SAP/JNK

Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro

“…Conversely, the pro-apoptotic effects of these prokineticins were always obtained at much lower concentrations (10e100 pM), with bell-shaped dose-response curves and no neurotoxic effects at higher concentrations (Cheng et al, 2012;Gasser et al, 2015;Severini et al, 2015). Because the affinity of Bv8 for PKR1 and PKR2 is about 0.5e0.7 nM and that of PK2 is tenfold lower (Negri et al, 2007), it is possible that only full (nanomolar) concentrations of Bv8 or PK2 may be able to activate a significant fraction of receptors and their pro-survival ERK1/2 and Akt transduction pathways (Negri et al, 2005).…”

“…In cardiac tissue, Bv8 was able to attenuate cardiomyocyte oxidative stress (Urayama et al, 2008) and, in a very recent report, a novel PKR1 agonist was demonstrated to prevent myocardial infarction in mice via an angiogenic mechanism (Gasser et al, 2015). However, reports also exist showing that Bv8/PK2 prokineticins induce a proinflammatory phenotype in mouse macrophages (Martucci et al, 2006), exacerbate the infarct volume in rats subjected to transient or permanent cerebral focal ischemia (Cheng et al, 2012), or reduce cell viability in primary rat cortical cultures (Severini et al, 2015). In these latter studies, prokineticin receptor blockers were able to protect against post-ischemic cell death (Cheng et al, 2012) or amyloid beta-induced neurotoxicity (Severini et al, 2015).…”

“…Because the affinity of Bv8 for PKR1 and PKR2 is about 0.5e0.7 nM and that of PK2 is tenfold lower (Negri et al, 2007), it is possible that only full (nanomolar) concentrations of Bv8 or PK2 may be able to activate a significant fraction of receptors and their pro-survival ERK1/2 and Akt transduction pathways (Negri et al, 2005). Along this line, the harmful effects of picomolar concentrations of PK2 have been suggested to be contributed by its unique effects on the SAP/JNK pathway under excitotoxic or OGD conditions (Cheng et al, 2012), whereas the pro-survival effects of prokineticins in the nanomolar range appear to require activation of the ERK1/2 and Akt signalling pathways (Melchiorri et al, 2001;Urayama et al, 2008;Gasser et al, 2015); this study). Other mechanisms are also possible: for example, the hyperalgesic effects of very low (femtomolar) concentrations of Bv8 are at least partly mediated by activation of the TRPV1 receptor , which has been shown to produce toxic effects and exacerbate OGD injury in our organotypic hippocampal slices (Landucci et al, 2011).…”

“…Hypoxic conditions in human adrenal carcinoma (LeCouter et al, 2001) or experimental stroke (Cheng et al, 2012) are known to induce the transcription of prokineticins. However, the results of experimental studies are conflicting on whether these chemokines may exert a protective or deleterious role in neurodegeneration.…”

“…Bv8 has been shown to protect against NMDA excitotoxicity in cerebellar granule cell cultures (Melchiorri et al, 2001), to protect cardiomyocytes against oxidative stress (Urayama et al, 2008), and to promote neurogenesis in the olfactory bulb (Ng et al, 2005). On the other hand, PK2 induces a proinflammatory phenotype in mouse macrophages (Martucci et al, 2006) and worsens the infarct volume, central inflammation and the behavioural outcome in models of stroke in vivo (Cheng et al, 2012).…”