Connexins-Based Hemichannels/Channels and Their Relationship with Inflammation, Seizures and Epilepsy
Abstract
:1. Molecular and Cellular Characteristics of Connexins-Based Hemichannels and Channels
2. Connexins-Based Hemichannels/Channels and Neuroinflammation
3. Blockers of Connexins-Based Channels/Hemichannels as Anticonvulsive and Antiepileptic Therapeutic Targets in Different Models of Seizures and Epilepsy
Blocker(s) of Cxs-Based Hemichannels or Channels | Seizure or Epilepsy Model | Technique/Brain Region | Main Results | Citation |
---|---|---|---|---|
Carbenoxolone (10 μM) and quinine (35 μM) administered through a piece of filter paper covering the cortical surface | In vivo: local application of crystalline 4-AP on the surface of the cortex | Electrocorticography (ECoG) in the brains of adult Wistar rats (male and female, 30–40 days old, 200–250 g) | Anticonvulsive effect of carbenoxolone (reduced the generation of seizure discharges); quinine decreased summated ictal activity and the amplitudes of seizure discharges | [125] |
Carbenoxolone (150 mM) and meclofenamic acid (50 mM) administered through a cannula implanted in the right motor cortex | In vivo: a model of refractory focal cortical epilepsy induced with tetanus toxin (50 ng/0.5 μL, pH 7.5) in 2% bovine serum albumin | Intracranial electroencephalography (iEEG) in the right motor cortex of adult Sprague-Dawley rats (240–320 g) | Reduced the percentage of seizure time | [126] |
Quinine (200, 400 or 1000 nmol) administered through a cannula implanted in the ventricle of the brain | In vivo: a model of epilepsy induced by 300 IU of crystallized penicillin | Epidural EEG in adult Wistar rats (male, 4 months) | Decreased the amplitude and frequency of epileptiform spikes and attenuated convulsive behavior | [127] |
Carbenoxolone injection (50 nmol) administered through a cannula implanted in the entorhinal cortex | In vivo: a model of seizures induced by 4-aminopyridine (10 nmol) administered through a cannula implanted in the entorhinal cortex | Epidural EEG and iEEG in the entorhinal cortex of adult Wistar rats (male, 250–350 g) | Decreased the amplitude and frequency of epileptiform discharges and the number and duration of epileptiform trains | [128] |
Carbenoxolone, Gap 27 (mimetic amino acid residues 201–211, SRPTEKTIFII) and SLS (amino acid residues 180–195, SLSAVYTCKRDPCPHQ) peptides | In vitro: epileptiform activity induced in organotypic hippocampal slice cultures by stimulation | Extracellular recordings from the CA1 and CA3 regions of hippocampal slices from 7-day-old Wistar rats | Carbenoxolone inhibited both spontaneous and evoked seizure-like events; the Cx43 mimetic peptides selectively attenuated spontaneous recurrent epileptiform activity after prolonged (10 h) treatment | [146] |
Quinine injection (35 pmol) administered through a cannula implanted in the entorhinal cortex | In vivo: a model of seizures induced by 4-aminopyridine (10 nmol) administered through a cannula implanted in the entorhinal cortex | Epidural EEG and iEEG in the entorhinal cortex of adult Wistar rats (male, 250–350 g) | Decreased the amplitude and frequency of discharge trains and blocked seizure behavior in five of six rats | [129] |
Cx43 mimetic peptide (5 and 50 μM, sufficient to block hemichannels, VDCFLSRPTEKT, extracellular loop two of Cx43) | In vitro: a model of epileptiform injury induced by bicuculline methochloride (BMC) (48 h exposure to 100 μM) in hippocampal slices cultures from 6- to 8-day-old Wistar rats | Measurement of cell death after epileptiform activity (fluorescence signal) and immunohistochemistry for microtubule-associated protein (MAP2) | Exerted a protective effect in the CA1 region during the recovery period (24 h after BMC treatment) | [147] |
Carbenoxolone (20 mg/kg, i.p.) once a day for 14 days | In vivo: a model of posttraumatic epilepsy induced by ferric ions (microinjection of 10 μL of 0.1 M FeCl3 solution into the sensorimotor area) | Evaluation of convulsive behavior according to the Racine scale in adult male Sprague-Dawley rats aged 6–8 weeks and weighing 220–250 g | Ameliorated convulsive behavior score in rats | [130] |
Carbenoxolone (50 nmol) and quinine (35 pmol) administered through a guide cannula in the entorhinal cortex (0.2 μL/min for 5 min) | In vivo: a pilocarpine-induced model of temporal lobe epilepsy (1.2 mg/μL pilocarpine hydrochloride in a total volume of 2 μL, intracerebroventricular (i.c.v.) | iEEG in the hippocampus of epileptic adult Wistar rats (male, 190–200 g) | Decreased the number of Fast Ripples (FR) events and oscillation cycles per FR event | [150] |
Carbenoxolone (0.2 mM) | In vitro: Neocortical slices | Neocortical slices from epileptic patients (temporal and occipital regions) | Strongly decreased the incidence of FR events | [152] |
In silico: a small network of 256 multicompartment cells | Simulated networks containing only pyramidal cells, coupled only by axonal gap junctions, and without chemical synapses or interneurons | The network produced FR events via a cluster of axonal Cx-based channels (gap junctions) | ||
Carbenoxolone (40 mg/kg, i.p.) and carbenoxolone + valproic acid (300 mg/kg, i.p.) | In vivo: a kindling model of epilepsy induced by pentylenetetrazole (35 mg/kg, i.p.) | Epidural EEG in Wistar rats (female, 12–15 weeks old, 200 ± 50 g) | Carbenoxolone prevented generalized seizures and reduced seizure stage, seizure duration and spike frequency; no significant difference between carbenoxolone + valproic acid and valproic acid | [131] |
Carbenoxolone (50 mg/kg, i.p., for 3 days) and quinine (50 mg/kg, i.p. for 3 days) | In vivo: a lithium/pilocarpine-induced Status epilepticus (SE) model (i.p. injection of 50 mg/kg pilocarpine 18–20 h after the i.p. injection of 127 mg/kg lithium chloride) | iEEG in the hippocampus of adult Sprague-Dawley rats (male) | Reduced the spectral power of FR events 10 min after SE | [151] |
Coadministration of valproate (VPA), phenytoin (PHT), or carbamazepine (CBZ) at subtherapeutic doses (i.p.) with carbenoxolone (60 mg/kg, i.p., 5 mL/kg) or quinine (40 mg/kg, i.p., 5 mL/kg) | In vivo: maximal electroshock (MES)-induced (frequency of 60 Hz, pulse width of 0.6 ms, shock duration of 0.6 s, and a current of 90 mA) and pentylenetetrazole (PTZ)-induced (70 mg/kg, i.p.) models of seizures | EEG and power spectral analysis in Wistar rats (male, 270–300 g) | Quinine increased the anticonvulsant activity of VPA, PHT and CBZ to generalized tonic-clonic seizures in the MES-induced model and the anticonvulsant activity of CBZ only to generalized tonic-clonic seizures in the PTZ-induced model | [132] |
TAT-Gap 19 (200 mM for in vitro experiments; 12 mM intrahippocampal and 1 mM in a total volume of 1 μL i.c.v. for in vivo experiments); TAT-Gap19 (25 or 50 mg/kg i.p., electrical stimulation for in vivo experiments) | In vitro: pilocarpine (15 μM) administration in acute brain slices; In vivo: pilocarpine model in mice and rats (12 mM, intra hippocampal) Limbic psychomotor seizures by corneal stimulation | In vitro: ethidium bromide uptake experiments in acute brain slices from Glial Fibrillary Acidic Protein-enhanced Green Fluorescent Protein (GFAP-eGFP) transgenic mice (both genders, 2 months old); In vivo: video-EcoG analysis (seizure duration) or modified Racine’s scale evaluation (to score kindling-induced behavioral changes) in NMRI mice (male, 20–30 g) and, video-EcoG and Racine scale evaluation of convulsive behavior in Wistar rats (male, 250–300 g) | In vitro: dye uptake experiments demonstrated that astroglial Cx43 hemichannels open in response to pilocarpine, and this was inhibited by TAT-Gap19. In vivo: TAT-Gap19 suppressed seizures and decreased D-serine concentrations; these effects were reversed by exogenous D-serine administration, and a similar effect was observed for the electrical stimulation model | [160] |
In vitro experiments: Carbenoxolone (200 mM) quinine (100 mM) and La(NO3)3 (a blocker of Cx-based hemichannels) In vivo experiments: carbenoxolone (100 mg/kg) and quinine (40 mg/kg) | In vitro: low-Mg2+-induced epilepsy model In vivo: Wistar Albino Glaxo/ Rijswijk (WAG/Rij) rat model of absence epilepsy | Field potential recordings, evaluation of seizure-like events (SLEs) in hippocampal-entorhinal slices from Wistar rats (11–14 days old); epidural EEG (frontal and parietal cortex) in WAG/Rij rats (female, 11–12 months old, 195–210 g); recordings of bilaterally synchronous spike-wave discharges (SWDs) | Carbenoxolone prevented the occurrence of SLEs and aggravated seizures in non-convulsive absence epilepsy; quinine did not prevent SLEs but increased the number and total time of SWDs and decreased the length of the interictal intervals; La3+ completely abolished SLEs | [159] |
4. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Medina-Ceja, L.; Salazar-Sánchez, J.C.; Ortega-Ibarra, J.; Morales-Villagrán, A. Connexins-Based Hemichannels/Channels and Their Relationship with Inflammation, Seizures and Epilepsy. Int. J. Mol. Sci. 2019, 20, 5976. https://doi.org/10.3390/ijms20235976
Medina-Ceja L, Salazar-Sánchez JC, Ortega-Ibarra J, Morales-Villagrán A. Connexins-Based Hemichannels/Channels and Their Relationship with Inflammation, Seizures and Epilepsy. International Journal of Molecular Sciences. 2019; 20(23):5976. https://doi.org/10.3390/ijms20235976
Chicago/Turabian StyleMedina-Ceja, Laura, Juan C. Salazar-Sánchez, Jorge Ortega-Ibarra, and Alberto Morales-Villagrán. 2019. "Connexins-Based Hemichannels/Channels and Their Relationship with Inflammation, Seizures and Epilepsy" International Journal of Molecular Sciences 20, no. 23: 5976. https://doi.org/10.3390/ijms20235976