Table 1.
Summary of studies of Cx43 hemichannels and Px1 channels and purinergic receptors P2X4 and P2X7.
| Species | Age | Paradigm | Hemichannel activity/expression | Drug/knockout | Drug/knockout effect | References | |
|---|---|---|---|---|---|---|---|
| Connexin 43 (Cx43) | Rat primary astrocyte culture | Embyronic day (E) 9 | Metabolic inhibition | ↑ Cx43 hemichannel opening during metabolic inhibition | Contreras et al., 2002 | ||
| Rat primary astrocyte culture | P1/2 | Conditioned medium from LPS-activated microglia or TNF-α and IL-1β | ↑ Cx43 hemichannel activity 24 h after treatment | Retamal et al., 2007 | |||
| Rat primary astrocyte culture | P1/2 | Hypoxia and artificial cerebrospinal fluid medium mimicking ischemic conditions | ↑ Cx43 hemichannel opening 1 h after reoxygenation | Orellana et al., 2010* | |||
| Human microvascular endothelial cells | Hypoxic acidic ion-shifted ringer solution | ↑ ATP release from Cx43 hemichannels during treatment and after reperfusion | Kim and Green, 2016* | ||||
| C6 glioma cells transfected with Cx43 | Voltage activation of Cx43 hemichannels | ↑ ATP release from Cx43 hemichannels | Kang et al., 2008 | ||||
| Human adult retinal pigment epithelial cells | High glucose, TNF-α and IL-1β | ↑ ATP release from Cx43 hemichannels | Peptide 5 (5–50 μM), administered at the same time as high glucose and cytokine treatment | ↓ NLRP3 oligomerization ↓ Cytokine release |
Mugisho et al., 2018 | ||
| Mouse acute brain slice | 8–12 weeks | S. aureus in vivo intracerebral inoculation | ↑ Cx43 hemichannel activity | Karpuk et al., 2011* | |||
| Sheep | Near-term | Carotid artery occlusion | ↑ mRNA expression (6 h after end of occlusion) | Peptide5 i.c.v. (50 μmol/kg over 1 h, then 50 μmol/kg over 24 h) started 90 min after end of occlusion | ↑ Neuronal and oligodendrocyte survival Improved electroencephalogram recovery ↓ Seizure burden |
Davidson et al., 2012; Galinsky et al., 2017 | |
| Sheep | Near-term | Carotid artery occlusion | Peptide5 i.c.v. (50 μmol/kg over 1 h, then 50 μmol/kg over 24 h) started 3 h after end of occlusion | ↓ Seizure burden | Davidson et al., 2015a | ||
| Sheep | Near-term | Carotid artery occlusion | Peptide5 i.c.v. (50 μmol/kg/h) given 1 h before, and during occlusion only | No neuroprotection | Davidson et al., 2013b | ||
| Sheep | Preterm | Umbilical cord occlusion | Peptide5 i.c.v. (50 μmol/kg over 1 h, then 50 μmol/kg over 24 h) started 90 min after end of occlusion | ↑ Neuronal and oligodendrocyte Improved electroencephalogram recovery |
Davidson et al., 2013a | ||
| Rat | P7 | Common carotid artery ligation and hypoxia | ↑ Protein expression (24–48 h after HI) | Wang et al., 2014 | |||
| Rat | P7 | Common carotid artery ligation and hypoxia | ↑ Protein expression (8 h to 7 d after HI) | Gap 26 i.p. (50 μg/kg, 1 h) before HI | ↓ Infarct size ↑ Motor and memory scores |
Li et al., 2015 | |
| Rat | P10 | Acute hypoxia | No change (10 min to 35 d after HI) | Zeinieh et al., 2010 | |||
|
Pannexin 1 (Px1) |
Rat primary neurons | P20-25 | N-methyl-D-aspartate receptor (NMDAR) activation | ↑ Px1 channel opening | Thompson et al., 2008 | ||
| Rat primary neurons | P15-20 | OGD | ↑ Px1 channel opening during OGD | Thompson et al., 2006 | |||
| Mouse hippocampal slice | P13-14 | High K+ medium | ↑ Px1 channel opening | Santiago et al., 2011 | |||
| Mouse primary astrocytes | OGD | Probenecid (10 μM) | ↓ IL-1β release ↓ NLRP3 protein expression |
Jian et al., 2016 | |||
| Mouse acute brain slice | 8–12 weeks | S. aureus in vivo intracerebral inoculation | ↑ Px1 channel activity | Karpuk et al., 2011* | |||
| Xenopus oocytes expressing Px1 | High K+ medium | ↑ ATP release during treatment from Px1 channels | Bao et al., 2004 | ||||
| Rat primary astrocyte culture | P1/2 | Hypoxia and artificial cerebrospinal fluid medium mimicking ischemic conditions | No Px1 channel opening at 1 h after reoxygenation | Orellana et al., 2010* | |||
| Human microvascular endothelial cells | Hypoxic acidic ion-shifted ringer solution | ↑ ATP release from Px1 channels during treatment but not after reperfusion | Kim and Green, 2016* | ||||
| Mice | Adult | MCAO | Mefloquine i.p. (1 mg/kg/d) given during the start of MCAO | ↓ Infarction size ↑ Motor scores * No additive effect with P2X7R blockade |
Cisneros-Mejorado et al., 2015a* | ||
| Rat | Adult | MCAO | Probencid (i.v., 2 mg/kg) given before reperfusion | ↑ Neuronal survival | Wei et al., 2015 | ||
| Mice | Adult | MCAO | ↑ Px1 protein expression in females vs. male on ischemic and non-ischemic hemispheres | Probenicid i.p. (250 mg/kg) at 1.5 and 5 h | ↓ Infarct volume (female only) | Freitas-Andrade et al., 2017 | |
| Purinergic receptor (P2X4R) | Rat hippocampal slice | P8-10 | OGD | ↑ Protein expression at 24 h | Cavaliere et al., 2003 | ||
| Mice | Adult | MCAO | ↑ Protein expression at 6, 24, and 72 h | Global P2X4R knockout Myeloid cell P2X4R knockout |
↓ Infarct volume ↓ IL-1β and TNF-α release ↓ Infarct volume (females only) |
Verma et al., 2017 | |
| Rat primary microglia | P2-3 | TNP-ATP (20 μM) | ↓ Change of microglia to rounded morphology ↓ IL-1β and TNF-α protein expression |
Li et al., 2011 | |||
| Rat | P0 | Hypoxia | ↑ Protein expression from 4 h to 14 d | Li et al., 2011 | |||
| Rat | P3 | Common carotid artery occlusion and hypoxia | ↑ Protein expression 5 and 7 d after HI | Wixey et al., 2009 | |||
| Puringeric receptor (P2X7R) | Neuronal culture | OGD | Brilliant Blue G (50 nM or 5 μM) during OGD | ↓ Cell death | Arbeloa et al., 2012 | ||
| Rat | Adult | MCAO | Brilliant Blue G i.p. (30 mg/kg) during MCAO | ↓ Neuronal loss ↓ Infarct volume |
Arbeloa et al., 2012 | ||
| Rat | P0 | Intrauterine asphyxia | ↑ Protein expression immediately after asphyxia | Frizzo et al., 2010 | |||
| Rat | Adult | MCAO | ↑ Protein expression 4 d after MCAO | Franke et al., 2004 | |||
| Rat | Adult | Common carotid and vertebral arteries occlusion | ↑ Protein expression from 6 h to 7 d after insult | Brilliant Blue G treatment i.v. (50 mg/kg) administered daily, for 3 d immediately after occlusion | ↓ Neuronal loss | Yu et al., 2013 | |
| Rat | Adult | MCAO | A-438079 (3 μg, i.c.v.) or Brilliant Blue G (10 μg, i.c.v.), or Oxidized ATP (1 μg, i.c.v.), prior to HI | ↓ Neuronal loss ↑ Motor performance |
Chu et al., 2012 | ||
| Rat | Adult | MCAO | De novo expression of P2X7R on microglia | Melani et al., 2006 | |||
| Rat | Adult | Intracerebral hemorrhage | P2X7R siRNA i.c.v. (1,000 pmol) | ↓ NLRP3 inflammasome activation ↓ IL-1β and IL-18 release |
Feng et al., 2015 | ||
| Neuronal culture | OGD | ↑ Protein expression after 3, 6, and 12 h of OGD | Ye et al., 2017 | ||||
| Mice | Adult | Photothrombotic cerebral ischemia | ↑ Protein expression from 1 to 5 d after insult | Brilliant Blue G (45.5 mg/kg, i.p.) given at 1, 3, and 5 d | ↓ Infarct volume ↓ Protein expression of NLRP3, ASC, and caspase 1 p20 |
Ye et al., 2017 | |
| Mice | Adult | MCAO | Brilliant Blue G (30 mg/kg twice per day, i.p.) during MCAO | ↓ Infarction size ↑ Motor scores * No additive effect with Px1 blockade |
Cisneros-Mejorado et al., 2015a* | ||
| Mice | Adult | MCAO | P2X7R knockout | ↓ Microglia activation | Kaiser et al., 2016 |
*
Studies that report interactions between connexin hemichannels, pannexin channels, and/or purinergic receptors.