Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1 -- 3488 2023-05-31 18:16:14 |
2 format Meta information modification 3488 2023-06-01 03:37:04 |

Video Upload Options

Do you have a full video?


Are you sure to Delete?
If you have any further questions, please contact Encyclopedia Editorial Office.
García-Rodríguez, C.; Mujica, P.; Illanes-González, J.; López, A.; Vargas, C.; Sáez, J.C.; González-Jamett, A.; Ardiles, �.O. Central Nervous System Diseases and the Probenecid. Encyclopedia. Available online: (accessed on 05 December 2023).
García-Rodríguez C, Mujica P, Illanes-González J, López A, Vargas C, Sáez JC, et al. Central Nervous System Diseases and the Probenecid. Encyclopedia. Available at: Accessed December 05, 2023.
García-Rodríguez, Claudia, Paula Mujica, Javiera Illanes-González, Araceli López, Camilo Vargas, Juan C. Sáez, Arlek González-Jamett, Álvaro O. Ardiles. "Central Nervous System Diseases and the Probenecid" Encyclopedia, (accessed December 05, 2023).
García-Rodríguez, C., Mujica, P., Illanes-González, J., López, A., Vargas, C., Sáez, J.C., González-Jamett, A., & Ardiles, �.O.(2023, May 31). Central Nervous System Diseases and the Probenecid. In Encyclopedia.
García-Rodríguez, Claudia, et al. "Central Nervous System Diseases and the Probenecid." Encyclopedia. Web. 31 May, 2023.
Central Nervous System Diseases and the Probenecid

Probenecid is an old uricosuric agent used in clinics to treat gout and reduce the renal excretion of antibiotics. In recent years, probenecid has gained attention due to its ability to interact with membrane proteins such as TRPV2 channels, organic anion transporters, and pannexin 1 hemichannels, which suggests new potential therapeutic utilities in medicine. Some current functions of probenecid include their use as an adjuvant to increase the bioavailability of several drugs in the Central Nervous System (CNS). Numerous studies also suggest that this drug has important neuroprotective, antiepileptic, and anti-inflammatory properties, as evidenced by their effect against neurological and neurodegenerative diseases. In these studies, the use of probenecid as a Panx1 hemichannel blocker to reduce neuroinflammation is highlighted since neuroinflammation is a major trigger for diverse CNS alterations.

probenecid OAT pannexin 1 TRPV2

1. Neuroinflammation

Neuroinflammation refers to the inflammatory response within the CNS caused by various pathological factors or insults, including infection, trauma, ischemia, misfolded proteins, and toxins [1]. Inflammasomes are multimeric protein complexes in the cytosol of all cells, including stimulated immune cells that control the inflammatory response [2]. Inflammasomes activate the proinflammatory caspase-1 after their activation, which cleaves the propeptides pro-IL-1β and pro-IL-18 into the mature cytokines IL-1β and IL-18, which are then secreted by the cells. Caspase-1 can also induce pyroptosis, a proinflammatory form of cell death, which releases proinflammatory signals [3]. The inflammasomes can be classified by the stimuli that activate them. In the CNS, the inflammasome comprises the nucleotide-binding oligomerization domain, leucine-rich repeat-containing family proteins (NLRP), adaptor protein ASC, and caspase 1 enzyme [2]. Diverse stimuli, including toxins derived from viruses or bacteria, misfolded proteins (i.e., amyloid beta-peptide and alpha-synuclein), reactive oxygen species (ROS), and elevated extracellular ATP and K+ concentrations activate NLRP. The latter acts as membrane receptors that sense and bind these signals to recruit and promote inflammasome complex assembly [2][4]. Other stimuli, such as cytosolic double-stranded DNA (dsDNA), can activate the AIM2-like receptors (ALRs) [5], and pyrin receptors respond to toxins that covalently inactivate the small GTPase RhoA [6]. These receptors also activate and shape the different inflammasomes [3]. Once the inflammasome is activated, it can exert its proinflammatory function through the activation of caspase-1, the release of cytokines IL-1β and IL-18, leading to pyroptosis.
The outflow of ATP and the consequent activation of P2X7Rs also promotes inflammasome activation (NLRP3, ACS protein, and caspase-1 activation) [7], which leads to IL-1β production [2]. IL-1β, released into the extracellular space, reduces intercellular communication through gap junctions while increasing connexin 43 hemichannel activity in astrocytes [8]. The role of Panx1 hemichannels on the inflammasome was first described by Silverman et al., who studied caspase-1 activation using astrocytes and neurons expressing or lacking Panx1. In wild-type cells, normal caspase activation was induced by stimulation with elevated extracellular K+, whereas in Panx1-knockout cells, caspase activation was undetectable, which supports the idea that Panx1 hemichannels mediate inflammation [9]. Moreover, in that study, preincubation with 1 mM PBN completely prevented caspase-1 activation in neurons and astrocytes, which further confirmed that PBN can alleviate inflammation and showed that PBN is a new tool that can reduce cell death in a variety of CNS lesions and diseases [9].
Panx1 participates in ATP-induced ATP release, and the mechanism involves purinergic receptors (P2YRs) that are coupled with G-protein and activate phospholipase C and IP3 production. High levels of extracellular ATP induce a rapid outflow of K+ from the innate immune cells [9][10][11] and Ca2+ influx through purinergic receptors (i.e., P2X7Rs) that interact with Panx1 hemichannels [12]. Therefore, during tissue damage, an increased Panx1 hemichannel activity promoting ATP release acts as a central damage-associated molecular pattern (DAMP) [13][14]. Notably, in a neuron–astrocyte coculture system, the ATP and glutamate released from astrocytes treated with conditioned media from inflammatory microglia promote neuronal death by neuronal Panx1 hemichannel activation [15][16]. In addition, increased extracellular IL-1β functions as a signal to recruit more immune cells, which enhances neurotoxicity. In this sense, the Panx1 hemichannel plays a fundamental role in the initial events of the signaling and activation of the inflammasome [13][17], a multiprotein complex that mediates interleukin (IL-1β and IL-18) production and secretion [2]. This inflammatory environment negatively affects CNS cells as they deprive neurons of the astroglia’s protective spatial buffering function, which increases neuronal vulnerability and the incidence of neuronal death [15].
Regarding the inhibition of Panx1 hemichannels with PBN, it has been described that the activation of the inflammasome has been evaluated in cultured astrocytes after oxygen–glucose deprivation (OGD) using different PBN concentrations. In that study, the authors concluded that the protein expression levels of aquaporin-4 (AQP4), NLRP3, and caspase-1 increased concomitantly after 6 h of OGD. This increase was strongly inhibited by PBN treatment applied before OGD [7]. Additionally, PBN significantly improved astrocyte survival, and this was associated with reduced ROS production and NLRP3, caspase-1, and IL-1β expression. Recently, Zheng et al. described the protective effect of PBN by blocking Panx1 hemichannels in brain lesions by inhibiting the AIM2 neuronal inflammasome after a subarachnoid hemorrhage in rats. The PBN was administered orally (1 mg/mL in water, 50 mL final volume) and through intraperitoneal injections (1 mg/kg) twice, before and after 2 h of hemorrhage. PBN decreased the levels of the AIM-2 inflammasome, ASC protein, caspase 1, P2X7R, IL-18, IL1β, purinergic receptors, and reactive oxygen species (ROS) [18].
According to the above findings, inhibition at the early stages of the inflammatory process with PBN could be crucial to stop neuroinflammation and neuronal death, which is a common hallmark of several pathologies; thus, this opens the possibility of new uses of PBN.

2. Epilepsy

Epilepsy is one of the most common neurological disorders that affects brain function. It is characterized by spontaneous seizures leading to cognitive, neurological, and psychosocial consequences [19]. Epilepsy affects around 50 million people worldwide and is responsible for a 2–10% reduction in life expectancy [20]. Additionally, approximately one third of epileptic patients do not respond to any of the currently available antiepileptic drugs, and for them, the only option is brain surgery, if possible [21]. For this same reason, it is of great interest to be able to develop new therapies against this disease with a high prevalence in the world. PBN could be of interest in the pharmacology of epilepsy since Panx1 hemichannels are involved in the pathophysiology of epilepsy [22]. Panx1 contributes to the generation and prolongation of epileptic seizures [23][24]. In fact, Dossi et al. reported that the Panx1 hemichannel blockade with 1 mM of PBN inhibited the induction of ictal discharges (IDs) and decreased seizure frequency in cortical slices obtained from postoperative epileptogenic tissues of patients with epilepsy [25]. In the same study, a single 200 mg/kg PBN intraperitoneal injection decreased the frequency of spontaneous seizures in mice with temporal lobe epilepsy (TLE) treated with kainic acid. In another study, PBN was reported to decrease the onset and severity of seizures [26]. In mice injected with 80 mg/kg pentylenetetrazol (PTZ), a chemical kindling model of epilepsy, Aquilino et al. demonstrated that pretreatment with PBN reduced the severity of seizures and the time to reach stage 5 seizures on the Racine scale, while it increased the survival after the PTZ injection [26]. It is important to note the implication of the connexin gap junctions in epilepsy. The glial proliferation and reduced gap junctional communication that occurs in epilepsy can have detrimental consequences [27], which can be prevented or reversed by the connexin gap junction blocker carbenoxolone [28][29] that would further reduce the gap junctional communication worsening the cell–cell coupling scenario. Alternatively, the antiepileptic effect of carbenoxolone could be explained by its inhibitory effect on Panx1 hemichannels since there is evidence that carbenoxolone also blocks these hemichannels [30]. All this evidence supports the potential role of PBN as an antiepileptic agent (Table 1).
Table 1. Effects of PBN in Central Nervous System diseases.
Study Type of Study Study Model Doses or Concentration CNS Pathology Probenecid Effect
Aquilino et al., 2020 [26] In vivo Mice pretreated with PBN are exposed to 80 mg/kg de PTZ 250 mg/kg i.p. Epilepsy Decrease in seizures severity.
Biju et al., 2018 [31] In vivo, ex vivo MPTP mice/PBN and behavioral assessment and tyrosine hydroxylase (TH) neuron analysis 250 mg/kg i.p. PD Low-dose methylene blue has neuroprotective actions in PD.
Carrillo-Mora et al., 2010 [32] In vivo, ex vivo Coadministration of kynurenic acid and PBN in beta-amyloid peptide rats. Evaluation by locomotor, memory, and morphological tests 50 mg/kg i.h. or i.p. AD Improvements in spatial memory and decrease in neurodegenerative events.
Dossi et al., 2018 [25] Ex vivo, in vivo Postoperative samples of human tissue in patients with epilepsy
Mouse model with kainic acid of temporal lobe epilepsy (TLE)
1 mM
200 mg/kg i.p.
Epilepsy Significant decrease in epileptic discharges.
Flores-Muñoz et al., 2020 [33] Ex vivo Transgenic APP/PS1 mice were dissected in different histological sections, to which PBN was administered 100 μM EA Decrease in synaptic plasticity deficits and improvement in dendritic spine density and dendritic arborization.
Hainz et al., 2016 [34] In vivo Experimental autoimmune encephalomyelitis (EAE) mouse model–multiple sclerosis (MS) mouse model 200 mg/kg i.p. EAE/MS Significant decrease in inflammation and infiltrating T cells in the CNS.
Hainz et al., 2017 [35] In vivo Experimental autoimmune encephalomyelitis (EAE) mouse model–multiple sclerosis (MS) mouse model 200 mg/kg i.p. EAE/MS Decrease in inflammation and T-cell infiltration and increase in oligodendrocyte number.
Jian et al., 2016 [7] In vitro Primary neuron and astrocyte culture from newborn mice exposed to
oxygen–glucose deprivation/reoxygenation (OGD/RX)
5–10 μM Ischemia Inhibition of inflammasome and caspase 1 activities.
Karatas et al., 2013 [36] In vivo Experimental mice model of cortical spreading depression (CSD) induced by pinprick or KCl 60 μg i.c.v. Migraine/headache Suppression of trigeminovascular activation, dural mast cell degranulation, inflammation, and headache.
Shao et al., 2019 [37] Ex vivo MPTP mice/PBN and subsequent substantia nigra and striatum analysis 250 mg/kg i.p. PD Verification of the neuroprotective role of TLR4 in PD.
Silva-Adaya et al., 2011 [38] In vivo 6-OHDA-induced PD model mice, coadministration of PBN with L-kineurin 70 mg/kg i.p. PD Increase in CNS kynurenic acid levels.
Silverman et al., 2009 [9] In vitro Primary neuron and astrocyte culture. Culture of oocytes absent from follicular cells of Xenopus laevis frogs 2 mM NA Blockade of inflammasome activation and PANX1 currents.
Sun et al., 2001 [39] In vitro Analysis of fluorescein passage in bovine brain micro vessel endothelial cells (BBMEC) 100 μM NA Increase in the passage of fluorescein in BBMEC.
Tunblad et al., 2003 [40] In vivo PBN is administered using micro dialysis probes to evaluate its influence on the passage of morphine to the CNS in rats 20 mg/kg e.f.b.
20 mg/kg/h i.f.
NA Increase in morphine half-life by almost twice in rat brain.
Wei et al., 2015 [41] In vivo Cerebral ischemia/reperfusion (I/R) rat model 2 mg/kg i.p.
5 mg/kg gavage
0.1–1–10 mg/mL i.v.
Cerebral ischemia Reduction in CA1 neuron loss and inflammation.
Yu X. Y. et al., 2007 [42] Ex vivo Administration of cytosine with PBN in rats and evaluation of its role 200 μM AD Decreases in cytosine output.
Zhang et al., 2019 [43] In vivo Sepsis-associated encephalopathy (SAE) mouse model 50 mg/kg i.p. SAE Attenuation in neuroinflammatory response and cognitive impairments.

3. Parkinson’s Disease

Parkinson´s disease (PD) is the second most common neurodegenerative disorder affecting 2–3% of the population over 65 years of age; it is characterized by the deterioration of motor activities due to the progressive loss of dopaminergic neurons in the substantia nigra [44]. This condition causes a striatal dopamine deficiency, intracellular inclusions of α-synuclein, and the formation of Lewy bodies, which are the neuropathological hallmarks of PD [45]. PD has several stages, from mild tremors to absolute dependence [44]. Most PD cases are sporadic and associated with aging, whereas 5–10% of PD cases are genetic and associated with mutations in PARK genes, which encode proteins such as α-synuclein, LRRK2, parkin, PINK, and DJ-1 [44][45]. Furthermore, nongenetic risk factors include environmental toxins, pesticides, heavy metals, traumatic lesions, and bacterial or viral infections, which are closely associated with the inflammation that promotes the manifestation of Parkinson´s disease [46]. In this regard, Panx1- and connexin-based channels and inflammation have been proposed to be involved in PD [47]. Indeed, α-synuclein was found to induce the opening of Panx1 and connexin 43 hemichannels, and the intervention of these channels was suggested as a potential therapeutic target in α-synuclein-associated diseases [48].
On the other hand, the effects of the intraperitoneal administration of L-kynurenine (kynurenic acid precursor), a competitive antagonist of the glutamate receptor type (NMDAR), together with PBN was evaluated in a 6-hydroxydopamine (6-OHDA)-induced PD mice model. In that study, the coadministration of L-kynurenine and PBN at doses of 75 mg/kg and 50 mg/kg, respectively, for 7 days reduced the decay in the total dopamine levels and protected mice from striatal damage and neurodegeneration [38]. Silva-Adaya et al. concluded that the protective effects are due to the product of kynurenic acid, and the function of PBN was to increase kynurenic acid levels in the brain [38].
As mentioned above, PBN has also been used to increase 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) levels in the brain, and this can be used to generate a mouse model for PD. In that model, two studies were conducted. The first study examined the benefits of methylene blue when administered in an MPTP/PBN model mouse [31], and the second study evaluated the role of Toll-like receptors 4 (TLR4) in PD [37] (Table 1). The use of PBN as an alternative therapy for PD is not entirely clear, even though the disease is related to changes in Panx1 hemichannel activity. In that context, the use of PBN in these studies was aimed at increasing the bioavailability of other molecules in the CNS, either as a therapeutic agent for PD or as an adjuvant for the induction of the pathogenic mechanism in animal models of PD.

4. Alzheimer’s Disease (AD)

Among the neurological conditions affecting older adults, AD is the most prevalent chronic neurodegenerative disease and the most common cause of dementia worldwide. AD is characterized by brain atrophy and the accumulation of amyloid plaques and neurofibrillary tangles that constitute the hallmarks of the disease [49]. AD comprises several stages starting with recent memory loss and progressively advancing to affect other cognitive domains [50]. One of the earliest events that correlate with cognitive impairment is synaptic loss [51][52] due to the accumulation of soluble amyloid oligomers, which freely diffuse and bind to proteins in the brain [53]. Amyloid oligomers are aggregates of amyloid beta-peptide (Aβ), a fragment of 40–42 amino acids with great facility to self-aggregate generated from the proteolytic cleavage of amyloid precursor protein (APP) [54]. These aggregates subsequently form amyloid fibrils that constitute insoluble extracellular deposits called amyloid plaques [49]. Together with amyloid plaques, neurofibrillary tangles, formed by hyperphosphorylated Tau protein aggregates, constitute the brain lesions that appear in the brain structures that are important for cognitive function [55].
In that pathological context, the soluble Aβ oligomers impair synaptic plasticity by reducing the size and number of dendritic spines, which prevents long-term potentiation (LTP), promotes long-term depression (LTD), and leads to cognitive dysfunctions and an impaired spatial memory [53]. Interestingly, and as mentioned before, it has recently been proposed that Panx1 hemichannels could play an important role in that disease since they modulate the induction of excitatory synaptic plasticity and paracrine communication [56], which are two processes that are affected during the development of this disease. As a matter of fact, a study evaluated the in vitro effect of PBN in a mouse model of Alzheimer’s disease (transgenic mice carrying mutations in the APP and PSEN 1 genes), where it was observed that the acute blocking of Panx1 hemichannels with 100 µM PBN normalizes hippocampal synaptic plasticity and improves the morphology and density of dendritic spines [33]. Flores-Muñoz et al. also observed a reduction in the levels of the active form of the p38 MAPK, which is increased in the Alzheimer’s brain and is associated with the neurotoxic phase in early AD [57] (Hensley et al., 1999). However, the neurodegeneration hallmarks were not reduced by the acute PBN treatment, likely due to the form of administration, namely the in vitro treatment of brain slices. Thus, the direct effect of PBN in AD is still preliminary, and additional studies using prolonged forms of administration require further research. In another study, rats were treated with an intrathecal injection of amyloid-beta peptide that was coadministered with PBN and L-kynurenine (50 mg/kg/7 days and 75 mg/kg/7 days, respectively) to evaluate its effect on Aβ-induced neurotoxicity. Carrillo-Mora et al. described that those injected rats experienced an improved spatial memory and decreased reactive gliosis in the CA1 region of their hippocampi [32]. It should be noted that the study was focused on demonstrating the positive effects of kynurenic acid and its NMDAR antagonism in rats. Therefore, the protective actions were not exclusively linked to the use of PBN and were administered to interrupt the excretion of kynurenic acid from the CNS, and the objectives were similar to those of the studies mentioned for PD [38]. In the same line, various molecules including sodium azide, 2,4-dinitrophenol, verapamil, nifedipine, quinidine, MK-571 (leukotriene D4 receptor antagonist), and PBN were used to evaluate the passage through the BBB and brain availability of cytosine (CTS), an experimental treatment for AD. Yu et al. reported that the oral administration of 200 μM PBN increased the uptake and decreased the outflow of CTS from the rat brain through endothelial cells [42].
The use of PBN as a therapeutic agent for AD has still not been entirely explored since, in most of the exposed cases, it was used to increase the bioavailability in the CNS of other molecules, and in the case where it was administered as a mono drug for AD treatment, it did not achieve sufficient benefits, and the evidence is still preliminary.

5. Other Diseases

PBN has also been used in several animal and cell models of CNS disorders. For instance, PBN was shown to have a protective effect in a Huntington’s disease (HD) model, a progressive and autosomal dominant neurodegenerative disorder caused by an expanded CAG repeat in the huntingtin gene which encodes an abnormally long polyglutamine repeat in the huntingtin protein. HD is characterized by movement disorders (including chorea and a loss of coordination) and cognitive decline defects [58]. In the study, Vamos et al., using the N171-82Q transgenic HD animal model, found that PBN administration improved motor behavior, increased cell survival, and significantly reduced neuronal loss and the number of intranuclear neuronal aggregates [59].
PBN was also used in an animal model of multiple sclerosis (MS), an experimental autoimmune encephalomyelitis (EAE) model [34][35]. MS is a progressive, autoimmune neurologic disorder of the CNS characterized by demyelination, axon degeneration, and neuroinflammation [60]. Autoreactive T helper cells (Th1 and Th17), which cross the BBB, are responsible for the inflammatory and demyelinating condition in MS. Hainz et al. showed that pretreatment with PBN prevents some early EAE symptoms, including motor abnormalities and diminished T cell numbers in the CNS and cell infiltrates in the spinal cord [34]. Moreover, in pronounced EAE after 20 days of treatment with PBN, inflammation, T cell infiltration, and oligodendrocyte cell loss were reduced, indicating that PBN prolonged neuronal and glia survival and prevented the progression of clinical symptoms associated with the EAE model of MS [35]. Interestingly, in that study, the effects of PBN were mediated by Panx1 hemichannel inhibition, confirming that PBN alleviates MS symptoms by reducing neuroinflammation.
In another study, Wei et al. evaluated the protective effect of the intravenous, intraperitoneal, and gavage administration of PBN against cerebral ischemia/reperfusion (I/R) injury in rats. Independent of the route of administration, PBN decreased neuronal death in the CA1 area, and some inflammatory markers were induced by I/R [41]. A similar study evaluated PBN treatment in a mouse model of sepsis-associated encephalopathy (SAE) induced by cecal ligation and puncture, which was characterized by cerebral dysfunction with varying neurological symptoms. In that study, Zhang et al. reported that PBN reduced the overexpression of inflammatory mediators such as the tumor necrosis factor-α (TNF-α), IL-6, and IL-1β in the hippocampus, which appear when acute cerebral dysfunction occurs [43]. Furthermore, cognitive impairment was also reduced after PBN administration. Notably, the reduced neuroinflammatory response and ATP release were mediated by a Panx1 hemichannel blockade, which suggests that PBN could be a promising therapeutic approach for treating inflammation during the cerebral dysfunction of sepsis.
On the other hand, PBN also has been used to alleviate migraine headaches [36]. Cortical spreading depression is thought to cause the migraine aura by activating perivascular trigeminal nerves [61]. In this report, Karatas et al. identified a signaling cascade involving the neuronal Panx1 hemichannel opening and caspase-1 activation followed by high-mobility group box 1 (HMGB1) release from neurons and nuclear factor κB activation in astrocytes [36]. Panx1 hemichannel blockers, including PBN, suppressed this inflammatory response and abolished the headaches, which further supports the relationship between Panx1 hemichannels and inflammation.
In addition to its use in the mentioned diseases, PBN has also been used in other studies to discriminate between the effect of connexin and Panx1 hemichannels since PBN only blocks Panx1 hemichannels and not the gap junction channels formed by Panx1 [62]. Thus, it was possible to determine that connexins, but not Panx1 hemichannels, have a very important role in the generation of endogenous spontaneous electrical activity in subplate neurons in the developing brain [63].


  1. Disabato, D.J.; Quan, N.; Godbout, J.P. Neuroinflammation: The devil is in the details. J. Neurochem. 2016, 139 (Suppl. 2), 136–153.
  2. Broz, P.; Dixit, V.M. Inflammasomes: Mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 2016, 16, 407–420.
  3. Voet, S.; Srinivasan, S.; Lamkanfi, M.; van Loo, G. Inflammasomes in neuroinflammatory and neurodegenerative diseases. EMBO Mol. Med. 2019, 11, e10248.
  4. Lang, Y.; Chu, F.; Shen, D.; Zhang, W.; Zheng, C.; Zhu, J.; Cui, L. Role of Inflammasomes in Neuroimmune and Neurodegenerative Diseases: A Systematic Review. Mediat. Inflamm. 2018, 2018, 1549549.
  5. Hornung, V.; Ablasser, A.; Charrel-Dennis, M.; Bauernfeind, F.; Horvath, G.; Caffrey, D.R.; Latz, E.; Fitzgerald, K.A. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 2009, 458, 514–518.
  6. Xu, H.; Yang, J.; Gao, W.; Li, L.; Li, P.; Zhang, L.; Gong, Y.-N.; Peng, X.; Xi, J.J.; Chen, S.; et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature 2014, 513, 237–241.
  7. Jian, Z.; Ding, S.; Deng, H.; Wang, J.; Yi, W.; Wang, L.; Zhu, S.; Gu, L.; Xiong, X. Probenecid protects against oxygen–glucose deprivation injury in primary astrocytes by regulating inflammasome activity. Brain Res. 2016, 1643, 123–129.
  8. Bennett, M.V.; Garré, J.M.; Orellana, J.A.; Bukauskas, F.F.; Nedergaard, M.; Giaume, C.; Sáez, J.C. Connexin and pannexin hemichannels in inflammatory responses of glia and neurons. Brain Res. 2012, 1487, 3–15.
  9. Silverman, W.R.; de Rivero Vaccari, J.P.; Locovei, S.; Qiu, F.; Carlsson, S.K.; Scemes, E.; Keane, R.W.; Dahl, G. The Pannexin 1 Channel Activates the Inflammasome in Neurons and Astrocytes. J. Biol. Chem. 2009, 284, 18143–18151.
  10. Walev, I.; Reske, K.; Palmer, M.; Valeva, A.; Bhakdi, S. Potassium-inhibited processing of IL-1 beta in human monocytes. EMBO J. 1995, 14, 1607–1614.
  11. Pétrilli, V.; Papin, S.; Dostert, C.; Mayor, A.; Martinon, F.; Tschopp, J. Activation of the NALP3 inflammasome is triggered by low intracellular potassium concentration. Cell Death Differ. 2007, 14, 1583–1589.
  12. Iglesias, R.; Locovei, S.; Roque, A.; Alberto, A.P.; Dahl, G.; Spray, D.C.; Scemes, E. P2X7receptor-Pannexin1 complex: Pharmacology and signaling. Am. J. Physiol. Cell Physiol. 2008, 295, C752–C760.
  13. Adamson, S.E.; Leitinger, N. The role of pannexin1 in the induction and resolution of inflammation. FEBS Lett. 2014, 588, 1416–1422.
  14. Gombault, A.; Baron, L.; Couillin, I. ATP release and purinergic signaling in NLRP3 inflammasome activation. Front. Immunol. 2012, 3, 414.
  15. Orellana, J.A.; Froger, N.; Ezan, P.; Jiang, J.X.; Bennett, M.V.; Naus, C.C.; Giaume, C.; Sáez, J.C. ATP and glutamate released via astroglial connexin 43 hemichannels mediate neuronal death through activation of pannexin 1 hemichannels. J. Neurochem. 2011, 118, 826–840.
  16. Orellana, J.A.; Shoji, K.F.; Abudara, V.; Ezan, P.; Amigou, E.; Sáez, P.J.; Jiang, J.X.; Naus, C.C.; Sáez, J.C.; Giaume, C. Amyloid beta-induced death in neurons involves glial and neuronal hemichannels. J. Neurosci. 2011, 31, 4962–4977.
  17. Yang, Y.; Delalio, L.J.; Best, A.K.; Macal, E.; Milstein, J.; Donnelly, I.; Miller, A.M.; McBride, M.; Shu, X.; Koval, M.; et al. Endothelial Pannexin 1 Channels Control Inflammation by Regulating Intracellular Calcium. J. Immunol. 2020, 204, 2995–3007.
  18. Zheng, Y.; Tang, W.; Zeng, H.; Peng, Y.; Yu, X.; Yan, F.; Cao, S. Probenecid-Blocked Pannexin-1 Channel Protects against Early Brain Injury via Inhibiting Neuronal AIM2 Inflammasome Activation after Subarachnoid Hemorrhage. Front. Neurol. 2022, 13, 854671.
  19. Thijs, R.D.; Surges, R.; O’Brien, T.J.; Sander, J.W. Epilepsy in adults. Lancet 2019, 393, 689–701.
  20. Moshe, S.L.; Perucca, E.; Ryvlin, P.; Tomson, T. Epilepsy: New advances. Lancet 2015, 385, 884–898.
  21. Rugg-Gunn, F.; Miserocchi, A.; McEvoy, A. Epilepsy surgery. Pract. Neurol. 2020, 20, 4–14.
  22. García-Rodríguez, C.; Bravo-Tobar, I.D.; Duarte, Y.; Barrio, L.C.; Sáez, J.C. Contribution of non-selective membrane channels and receptors in epilepsy. Pharmacol. Ther. 2022, 231, 107980.
  23. Aquilino, M.S.; Whyte-Fagundes, P.; Zoidl, G.; Carlen, P.L. Pannexin-1 channels in epilepsy. Neurosci. Lett. 2019, 695, 71–75.
  24. Santiago, M.F.; Veliskova, J.; Patel, N.K.; Lutz, S.E.; Caille, D.; Charollais, A.; Meda, P.; Scemes, E. Targeting Pannexin1 Improves Seizure Outcome. PLoS ONE 2011, 6, e25178.
  25. Dossi, E.; Blauwblomme, T.; Moulard, J.; Chever, O.; Vasile, F.; Guinard, E.; Le Bert, M.; Couillin, I.; Pallud, J.; Capelle, L.; et al. Pannexin-1 channels contribute to seizure generation in human epileptic brain tissue and in a mouse model of epilepsy. Sci. Transl. Med. 2018, 10, eaar3796.
  26. Aquilino, M.S.; Whyte-Fagundes, P.; Lukewich, M.K.; Zhang, L.; Bardakjian, B.L.; Zoidl, G.R.; Carlen, P.L. Pannexin-1 Deficiency Decreases Epileptic Activity in Mice. Int. J. Mol. Sci. 2020, 21, 7510.
  27. Steinhäuser, C.; Seifert, G.; Bedner, P. Astrocyte dysfunction in temporal lobe epilepsy: K + channels and gap junction coupling. Glia 2012, 60, 1192–1202.
  28. Volnova, A.; Tsytsarev, V.; Ganina, O.; Vélez-Crespo, G.E.; Alves, J.M.; Ignashchenkova, A.; Inyushin, M. The Anti-Epileptic Effects of Carbenoxolone In Vitro and In Vivo. Int. J. Mol. Sci. 2022, 23, 663.
  29. Chen, W.; Gao, Z.; Ni, Y.; Dai, Z. Carbenoxolone pretreatment and treatment of posttraumatic epilepsy. Neural Regen. Res. 2013, 8, 169–176.
  30. Michalski, K.; Kawate, T. Carbenoxolone inhibits Pannexin1 channels through interactions in the first extracellular loop. J. Gen. Physiol. 2016, 147, 165–174.
  31. Biju, K.; Evans, R.C.; Shrestha, K.; Carlisle, D.C.; Gelfond, J.; Clark, R.A. Methylene Blue Ameliorates Olfactory Dysfunction and Motor Deficits in a Chronic MPTP/Probenecid Mouse Model of Parkinson’s Disease. Neuroscience 2018, 380, 111–122.
  32. Carrillo-Mora, P.; Méndez-Cuesta, L.A.; Perez-De La Cruz, V.; Fortoul-van Der Goes, T.I.; Santamaría, A. Protective effect of systemic l-kynurenine and probenecid administration on behavioural and morphological alterations induced by toxic soluble amyloid beta (25–35) in rat hippocampus. Behav. Brain Res. 2010, 210, 240–250.
  33. Flores-Muñoz, C.; Gómez, B.; Mery, E.; Mujica, P.; Gajardo, I.; Córdova, C.; Lopez-Espíndola, D.; Durán-Aniotz, C.; Hetz, C.; Muñoz, P.; et al. Acute Pannexin 1 Blockade Mitigates Early Synaptic Plasticity Defects in a Mouse Model of Alzheimer’s Disease. Front. Cell. Neurosci. 2020, 14, 46.
  34. Hainz, N.; Wolf, S.; Tschernig, T.; Meier, C. Probenecid Application Prevents Clinical Symptoms and Inflammation in Experimental Autoimmune Encephalomyelitis. Inflammation 2016, 39, 123–128.
  35. Hainz, N.; Wolf, S.; Beck, A.; Wagenpfeil, S.; Tschernig, T.; Meier, C. Probenecid arrests the progression of pronounced clinical symptoms in a mouse model of multiple sclerosis. Sci. Rep. 2017, 7, 17214.
  36. Karatas, H.; Erdener, S.E.; Gursoy-Ozdemir, Y.; Lule, S.; Eren-Koçak, E.; Sen, Z.D.; Dalkara, T. Spreading Depression Triggers Headache by Activating Neuronal Panx1 Channels. Science 2013, 339, 1092–1095.
  37. Shao, Q.-H.; Chen, Y.; Li, F.-F.; Wang, S.; Zhang, X.-L.; Yuan, Y.-H.; Chen, N.-H. TLR4 deficiency has a protective effect in the MPTP/probenecid mouse model of Parkinson’s disease. Acta Pharmacol. Sin. 2019, 40, 1503–1512.
  38. Silva-Adaya, D.; Perez-De La Cruz, V.; Villeda-Hernández, J.; Carrillo-Mora, P.; González-Herrera, I.G.; García, E.; Colín-Barenque, L.; Pedraza-Chaverrí, J.; Santamaría, A. Protective effect of l-kynurenine and probenecid on 6-hydroxydopamine-induced striatal toxicity in rats: Implications of modulating kynurenate as a protective strategy. Neurotoxicology Teratol. 2011, 33, 303–312.
  39. Sun, H.; Miller, N.W.; Elmquist, W.F. Effect of probenecid on fluorescein transport in the central nervous system using in vitro and in vivo models. Pharm. Res. 2001, 18, 1542–1549.
  40. Tunblad, K.; Jonsson, E.N.; Hammarlund-Udenaes, M. Morphine blood-brain barrier transport is influenced by probenecid co-administration. Pharm. Res. 2003, 20, 618–623.
  41. Wei, R.; Wang, J.; Xu, Y.; Yin, B.; He, F.; Du, Y.; Peng, G.; Luo, B. Probenecid protects against cerebral ischemia/reperfusion injury by inhibiting lysosomal and inflammatory damage in rats. Neuroscience 2015, 301, 168–177.
  42. Yu, X.Y.; Lin, S.G.; Chen, X.; Zhou, Z.W.; Liang, J.; Duan, W.; Chowbay, B.; Wen, J.Y.; Chan, E.; Cao, J.; et al. Transport of cryptotanshinone, a major active triterpenoid in Salvia miltiorrhiza Bunge widely used in the treatment of stroke and Alzheimer’s disease, across the blood-brain barrier. Curr. Drug Metab. 2007, 8, 365–378.
  43. Zhang, Z.; Lei, Y.; Yan, C.; Mei, X.; Jiang, T.; Ma, Z.; Wang, Q. Probenecid Relieves Cerebral Dysfunction of Sepsis by Inhibiting Pannexin 1-Dependent ATP Release. Inflammation 2019, 42, 1082–1092.
  44. Poewe, W.; Seppi, K.; Tanner, C.M.; Halliday, G.M.; Brundin, P.; Volkmann, J.; Schrag, A.E.; Lang, A.E. Parkinson disease. Nat. Rev. Dis. Primers 2017, 3, 17013.
  45. Jankovic, J.; Tan, E.K. Parkinson’s disease: Etiopathogenesis and treatment. J. Neurol. Neurosurg. Psychiatry 2020, 91, 795–808.
  46. Pajares, M.; IRojo, A.; Manda, G.; Boscá, L.; Cuadrado, A. Inflammation in Parkinson’s Disease: Mechanisms and Therapeutic Implications. Cells 2020, 9, 1687.
  47. Ahmadian, E.; Eftekhari, A.; Samiei, M.; Maleki Dizaj, S.; Vinken, M. The role and therapeutic potential of connexins, pannexins and their channels in Parkinson’s disease. Cell. Signal. 2019, 58, 111–118.
  48. Díaz, E.F.; Labra, V.C.; Alvear, T.F.; Mellado, L.A.; Inostroza, C.A.; Oyarzún, J.E.; Salgado, N.; Quintanilla, R.A.; Orellana, J.A. Connexin 43 hemichannels and pannexin-1 channels contribute to the α-synuclein-induced dysfunction and death of astrocytes. Glia 2019, 67, 1598–1619.
  49. Serrano-Pozo, A.; Frosch, M.P.; Masliah, E.; Hyman, B.T. Neuropathological Alterations in Alzheimer Disease. Cold Spring Harb. Perspect. Med. 2011, 1, a006189.
  50. Weintraub, S.; Wicklund, A.H.; Salmon, D.P. The Neuropsychological Profile of Alzheimer Disease. Cold Spring Harb. Perspect. Med. 2012, 2, a006171.
  51. Masliah, E.; Mallory, M.; Alford, M.; DeTeresa, R.; Hansen, L.; McKeel, D., Jr.; Morris, J. Altered expression of synaptic proteins occurs early during progression of Alzheimer’s disease. Neurology 2001, 56, 127–129.
  52. Terry, R.D.; Masliah, E.; Salmon, D.P.; Butters, N.; DeTeresa, R.; Hill, R.; Hansen, L.A.; Katzman, R. Physical basis of cognitive alterations in Alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment. Ann. Neurol. 1991, 30, 572–580.
  53. Sheng, M.; Sabatini, B.L.; Sudhof, T.C. Synapses and Alzheimer’s disease. Cold Spring Harb. Perspect Biol. 2012, 4, a005777.
  54. Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 2016, 8, 595–608.
  55. Johnson, K.A.; Fox, N.C.; Sperling, R.A.; Klunk, W.E. Brain imaging in Alzheimer disease. Cold Spring Harb. Perspect Med. 2012, 2, a006213.
  56. Yeung, A.K.; Patil, C.S.; Jackson, M.F. Pannexin-1 in the CNS: Emerging concepts in health and disease. J. Neurochem. 2020, 154, 468–485.
  57. Hensley, K.; Floyd, R.A.; Zheng, N.Y.; Nael, R.; Robinson, K.A.; Nguyen, X.; Pye, Q.N.; Stewart, C.A.; Geddes, J.; Markesbery, W.R.; et al. p38 kinase is activated in the Alzheimer’s disease brain. J. Neurochem. 1999, 72, 2053–2058.
  58. Jimenez-Sanchez, M.; Licitra, F.; Underwood, B.R.; Rubinsztein, D.C. Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb. Perspect. Med. 2017, 7, a024240.
  59. Vamos, E.; Voros, K.; Zadori, D.; Vecsei, L.; Klivenyi, P. Neuroprotective effects of probenecid in a transgenic animal model of Huntington’s disease. J. Neural Transm. 2009, 116, 1079–1086.
  60. Klineova, S.; Lublin, F.D. Clinical Course of Multiple Sclerosis. Cold Spring Harb. Perspect. Med. 2018, 8, a028928.
  61. Zhang, X.; Levy, D.; Noseda, R.; Kainz, V.; Jakubowski, M.; Burstein, R. Activation of Meningeal Nociceptors by Cortical Spreading Depression: Implications for Migraine with Aura. J. Neurosci. 2010, 30, 8807–8814.
  62. Sahu, G.; Sukumaran, S.; Bera, A.K. Pannexins form gap junctions with electrophysiological and pharmacological properties distinct from connexins. Sci. Rep. 2014, 4, 4955.
  63. Singh, M.B.; White, J.A.; McKimm, E.J.; Milosevic, M.; Antic, S.D. Mechanisms of Spontaneous Electrical Activity in the Developing Cerebral Cortex—Mouse Subplate Zone. Cereb. Cortex 2019, 29, 3363–3379.
Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to : , , , , , , ,
View Times: 160
Revisions: 2 times (View History)
Update Date: 01 Jun 2023