Central Nervous System Diseases and the Probenecid

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1		Alvaro O. Ardiles	--	3488	2023-05-31 18:16:14	\|
2	format	Jason Zhu	Meta information modification	3488	2023-06-01 03:37:04	\|

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11061516

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].

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