The Role of Prokineticin 2 in Oxidative Stress and in Neuropathological Processes

Abstract

The prokineticin (PK) family, prokineticin 1 and Bv8/prokineticin 2 (PROK2), initially discovered as regulators of gastrointestinal motility, interacts with two G protein-coupled receptors, PKR1 and PKR2, regulating important biological functions such as circadian rhythms, metabolism, angiogenesis, neurogenesis, muscle contractility, hematopoiesis, immune response, reproduction and pain perception. PROK2 and PK receptors, in particular PKR2, are widespread distributed in the central nervous system, in both neurons and glial cells. The PROK2 expression levels can be increased by a series of pathological insults, such as hypoxia, reactive oxygen species, beta amyloid and excitotoxic glutamate. This suggests that the PK system, participating in different cellular processes that cause neuronal death, can be a key mediator in neurological/neurodegenerative diseases. While many PROK2/PKRs effects in physiological processes have been documented, their role in neuropathological conditions is not fully clarified, since PROK2 can have a double function in the mechanisms underlying to neurodegeneration or neuroprotection. Here, we briefly outline the latest findings on the modulation of PROK2 and its cognate receptors following different pathological insults, providing information about their opposite neurotoxic and neuroprotective role in different pathological conditions.

Targeting Chemokines and Chemokine GPCRs to Enhance Strong Opioid Efficacy in Neuropathic Pain

“…Despite the deleterious effects demonstrated for chemokines in NP, there are recent literature studies that suggest a neuroprotective role of some chemokines in other pathological conditions [ 158 , 159 , 160 ]. For example, the chemokine CCL5 acting on a GPCR named GPR75 (G Protein-coupled Receptor 75), which does not belong to the chemokine receptor family and is expressed by neuronal cells, activates intracellular signaling pathways associated with neuroprotective effects [ 159 ].…”

Versatile Role of Prokineticins and Prokineticin Receptors in Neuroinflammation

“…The prokineticin system, involving the novel chemokine PK2 and its receptors PKR1 and PKR2, is involved in the pathogenesis of AD. It has been found that PK2 can act as a mediator of brain damage and that it plays a crucial role in amyloid-induced neuronal death [ 43 ]. Indeed, Aβ 1–42 increases the mRNA and protein levels of PK2/PKRs in vitro in primary cortical neurons (CNs), and the non-protein PKRs antagonist PC1 protects CNs from Aβ 1–42 -induced neurotoxicity in a dose-dependent manner by reducing PK2 overexpression.…”

“…Indeed, Aβ 1–42 increases the mRNA and protein levels of PK2/PKRs in vitro in primary cortical neurons (CNs), and the non-protein PKRs antagonist PC1 protects CNs from Aβ 1–42 -induced neurotoxicity in a dose-dependent manner by reducing PK2 overexpression. Moreover, the use of PC1 prevents the impairment of long-term potentiation (LTP) in the hippocampus of Tg2576 (TG, a transgenic mouse model of AD) mice compared to wild-type (WT) control mice and also reduces AMPA currents [ 43 ]. The same group showed in vivo that in a non-transgenic animal model of Alzheimer’s disease, induced by intracerebroventricular (i.c.v.)…”

“…The same group showed in vivo that in a non-transgenic animal model of Alzheimer’s disease, induced by intracerebroventricular (i.c.v.) Aβ 1–42 administration in rat, the prokineticin system is strongly upregulated in neurons and astrocytes of the hippocampus [ 43 ] and that pharmacological blockade of prokineticin receptors with PC1 protects against Aβ 1–42 induced cognitive deficits by reducing the overexpression of PK2 and PKRs. Subsequent identification of the PKR2 splice variant TM 4–7 in the rat hippocampus led to evidence that this PKR2 isoform is overexpressed in AD and is involved in disease progression [ 44 ].…”

“…The study showed that expression levels of PK2 in the hippocampus of AD patients are significantly higher than in cognitively normal control subjects. Interestingly, AD patients also have statistically higher serum PK2 levels than healthy individuals, suggesting that PK2 is an important potential biomarker for AD [ 43 ].…”