Changes of the GPR17 receptor, a new target for neurorepair, in neurons and glial cells in patients with traumatic brain injury

Abstract

Unveiling the mechanisms participating in the damage and repair of traumatic brain injury (TBI) is fundamental to develop new therapies. The P2Y-like GPR17 receptor has recently emerged as a sensor of damage and a key actor in lesion remodeling/repair in the rodent brain, but its role in humans is totally unknown. Here, we characterized GPR17 expression in brain specimens from seven intensive care unit TBI patients undergoing neurosurgery for contusion removal and from 28 autoptic TBI cases (and 10 control subjects of matched age and gender) of two university hospitals. In both neurosurgery and autoptic samples, GPR17 expression was strong inside the contused core and progressively declined distally according to a spatio-temporal gradient. Inside and around the core, GPR17 labeled dying neurons, reactive astrocytes, and activated microglia/macrophages. In peri-contused parenchyma, GPR17 decorated oligodendrocyte precursor cells (OPCs) some of which had proliferated, indicating re-myelination attempts. In autoptic cases, GPR17 expression positively correlated with death for intracranial complications and negatively correlated with patients' post-traumatic survival. Data indicate lesion-specific sequential involvement of GPR17 in the (a) death of irreversibly damaged neurons, (b) activation of microglia/macrophages remodeling the lesion, and (c) activation/proliferation of multipotent parenchymal progenitors (both reactive astrocytes and OPCs) starting repair processes. Data validate GPR17 as a target for neurorepair and are particularly relevant to setting up new therapies for TBI patients.

Is GPR17 a P2Y/Leukotriene Receptor? Examination of Uracil Nucleotides, Nucleotide Sugars, and Cysteinyl Leukotrienes as Agonists of GPR17

“…Recent studies highlight the importance of GPR17 in inflammation, neuronal damage sensing, neurorepair, food intake, and myelination (Lecca et al, 2008;Chen et al, 2009;Maekawa et al, 2010;Ren et al, 2012;Franke et al, 2013), but the true identity of the endogenous agonists of the receptor remains controversial. Ciana et al (2006) reported that GPR17 is activated by UDP, UDP-sugars, and cysteinyl leukotrienes, whereas Benned-Jensen and Rosenkilde (2010) reported activation of GPR17 with nucleotides but not with leukotrienes.…”

An introduction to the roles of purinergic signalling in neurodegeneration, neuroprotection and neuroregeneration

“…Intraneural injection of Ab has been shown to stimulate regeneration of primary sensory axons in the spinal cord (Wu et al, personal communication). The P2Y-like GPR17 has been identified as a sensor of damage of the CNS and participates in lesion repair in the rodent brain and in patients with traumatic brain injury (Franke et al, 2013).…”

Neurotransmitter signaling in white matter

“…In GM, P2Y1, and P2Y12 receptors are involved in astrogliosis in vivo (Franke et al, 2001), and the P2X receptor antagonist PPADS significantly decreases astrogliosis following spinal cord injury in vivo (Rodriquez-Zayas et al, 2012). However, P2X4 and P2Y12 receptors also regulate the microglial injury response (Franke et al, 2013), and the latter are expressed by oligodendrocytes/myelin (Amadio et al, 2006), making it difficult to distinguish specific cellular responses in vivo.Non-Glutamatergic/Purinergic Neurotransmitters in WM As described above, there are a variety of developmental functions now understood for WM glutamatergic/purinergic receptors (Table 1), but functional receptors for GABA-A/B, glycine and to a lesser extent nicotinic, 5-HT, dopamine and adrenoreceptors have also been reported in WM, although their functions remain mysterious (Tables 2 and 3). In a recent study, Fern and colleagues found that mRNA for three quarters of receptor subunits from a panel of non-glutamatergic/purinergic receptors were robustly expressed in WM glial cells, with some found at higher levels than in GM structures (Domingues et al, 2010).…”