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. Although the clinical use of probenecid has declined over the years, advances in its use in preclinical research indicate that it may be useful to improve conventional therapies in the psychiatric field where the drugs used have a low bioavailability, either because of a deficient passage through the blood–brain barrier or a high efflux from the CNS or also a high urinary clearance. This review summarizes the history, pharmacological properties, and recent research uses of probenecid and discusses its future projections as a potential pharmacological strategy to intervene in neurodegeneration as an outcome of neuroinflammation.

Dynamin-2 is a ubiquitously expressed GTP-ase that mediates membrane remodeling. Recent findings indicate that dynamin-2 also regulates actin dynamics. Mutations in dynamin-2 cause dominant centronuclear myopathy (CNM), a congenital myopathy characterized by progressive weakness and atrophy of skeletal muscles. However, the muscle-specific roles of dynamin-2 affected by these mutations remain elusive. Here we show that, in muscle cells, the GTP-ase activity of dynamin-2 is involved in de novo actin polymerization as well as in actin-mediated trafficking of the glucose transporter GLUT4. Expression of dynamin-2 constructs carrying CNM-linked mutations disrupted the formation of new actin filaments as well as the stimulus-induced translocation of GLUT4 to the plasma membrane. Similarly, mature muscle fibers isolated from heterozygous knock-in mice that harbor the dynamin-2 mutation p.R465W, an animal model of CNM, exhibited altered actin organization, reduced actin polymerization and impaired insulin-induced translocation of GLUT4 to the sarcolemma. Moreover, GLUT4 displayed aberrant perinuclear accumulation in biopsies from CNM patients carrying dynamin-2 mutations, further suggesting trafficking defects. These results suggest that dynamin-2 is a key regulator of actin dynamics and GLUT4 trafficking in muscle cells. Our findings also support a model in which impairment of actin-dependent trafficking contributes to the pathological mechanism in dynamin-2-associated CNM.

Muscular dystrophies (MDs) are a heterogeneous group of congenital neuromuscular disorders whose clinical signs include myalgia, skeletal muscle weakness, hypotonia, and atrophy that leads to progressive muscle disability and loss of ambulation. MDs can also affect cardiac and respiratory muscles, impairing life-expectancy. MDs in clude Duchenne muscular dystrophy, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy and limb-girdle muscular dystrophy. These and other MDs are caused by mutations in genes that encode proteins responsible for the structure and function of skeletal muscles, such as components of the dystrophin-glycoprotein-complex that connect the sarcomeric-actin with the extracellular matrix, allowing contractile force transmission and providing stability during muscle contraction. Consequently, in dystrophic conditions in which such proteins are affected, muscle integrity is disrupted, leading to local inflammatory responses, oxidative stress, Ca²⁺-dyshomeostasis and muscle degeneration. In this scenario, dysregulation of connexin hemichannels seem to be an early disruptor of the homeostasis that further plays a relevant role in these processes. The interaction between all these elements constitutes a positive feedback loop that contributes to the worsening of the diseases. Thus, we discuss here the interplay between inflammation, oxidative stress and connexin hemichannels in the progression of MDs and their potential as therapeutic targets.

Synaptic loss induced by soluble oligomeric forms of the amyloid β peptide (sAβos) is one of the earliest events in Alzheimer’s disease (AD) and is thought to be the major cause of the cognitive deficits. These abnormalities rely on defects in synaptic plasticity, a series of events manifested as activity-dependent modifications in synaptic structure and function. It has been reported that pannexin 1 (Panx1), a nonselective channel implicated in cell communication and intracellular signaling, modulates the induction of excitatory synaptic plasticity under physiological contexts and contributes to neuronal death under inflammatory conditions. Here, we decided to study the involvement of Panx1 in functional and structural defects observed in excitatory synapses of the amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic (Tg) mice, an animal model of AD. We found an age-dependent increase in the Panx1 expression that correlates with increased Aβ levels in hippocampal tissue from Tg mice. Congruently, we also observed an exacerbated Panx1 activity upon basal conditions and in response to glutamate receptor activation. The acute inhibition of Panx1 activity with the drug probenecid (PBN) did not change neurodegenerative parameters such as amyloid deposition or astrogliosis, but it significantly reduced excitatory synaptic defects in the AD model by normalizing long-term potentiation (LTP) and depression and improving dendritic arborization and spine density in hippocampal neurons of the Tg mice. These results suggest a major contribution of Panx1 in the early mechanisms leading to the synaptopathy in AD. Indeed, PBN induced a reduction in the activation of p38 mitogen-activated protein kinase (MAPK), a kinase widely implicated in the early neurotoxic signaling in AD. Our data strongly suggest that an enhanced expression and activation of Panx1 channels contribute to the Aβ-induced cascades leading to synaptic dysfunction in AD.

Enhanced activity and overexpression of Pannexin 1 (Panx1) channels contribute to neuronal pathologies such as epilepsy and Alzheimer’s disease (AD). The Panx1 channel ablation alters the hippocampus’s glutamatergic neurotransmission, synaptic plasticity, and memory flexibility. Nevertheless, Panx1-knockout (Panx1-KO) mice still retain the ability to learn, suggesting that compensatory mechanisms stabilize their neuronal activity. Here, we show that the absence of Panx1 in the adult brain promotes a series of structural and functional modifications in the Panx1-KO hippocampal synapses, preserving spontaneous activity. Compared to the wild-type (WT) condition, the adult hippocampal neurons of Panx1-KO mice exhibit enhanced excitability, a more complex dendritic branching, enhanced spine maturation, and an increased proportion of multiple synaptic contacts. These modifications seem to rely on the actin–cytoskeleton dynamics as an increase in the actin polymerization and an imbalance between the Rac1 and the RhoA GTPase activities were observed in Panx1-KO brain tissues. Our findings highlight a novel interaction between Panx1 channels, actin, and Rho GTPases, which appear to be relevant for synapse stability.

Hereditary myopathies are inherited disorders primarily affecting the skeletal muscle tissue. These are caused by mutations in different genes-encoding proteins that play important roles in muscle structure and function. Skeletal muscle weakness and hypotonia are typical clinical manifestations in most of hereditary myopathies. Histological features such as fiber type disproportion, myofibrillar disorganization, and structural abnormalities are usually observed in muscle biopsies of non-dystrophic myopathies, while fibrosis, fiber regeneration, wasting, and atrophy are characteristic of dystrophic myopathies. However, similar histopathological features may overlap in different hereditary myopathies. This is how mutations in a same gene can lead to different forms of hereditary myopathies and a same myopathic phenotype can derive from defects in different related genes making difficult a specific diagnosis. In this regard, understanding all aspects of hereditary myopathies can facilitate a better diagnosis and treatment. In this chapter, we offer a review of some of the most prevalent hereditary myopathies, highlighting clinical, histological, and molecular aspects of these muscle disorders.