Dapsone, More than an Effective Neuro and Cytoprotective Drug

1.1. Dapsone

Dapsone (4,4'diaminodiphenylsulfone) was synthesized for the first time in 1908 by Emil Fromm, who is considered the father of sulfones [11]; its chemical structure consists of a central sulfur atom attached to two carbon atoms (Fig. 1). The use of sulfones as therapeutic agents appeared long after dapsone synthesis. Dapsone is classified as an antibiotic to treat infections due to bacteria, yeasts, and parasites [4, 12]. This sulphone has a general use for the treatment of leprosy (Mycobacterium leprae) [13-15] and by having anti-inflammatory effects and inhibiting the production of reactive oxygen species (ROS), reducing the effect of eosinophil peroxidase on mast cells and negatively regulating neutrophil chemotaxis, this allows its use in the treatment of a wide variety of inflammatory and skin conditions. such as dermatitis herpetiformis and acne vulgaris [16] (Fig. 2).

Dapsone is rapidly and completely absorbed by the gastrointestinal tract with a bioavailability of nearly 90%. Peak serum concentrations are achieved between 2 to 8 hours after administration and its elimination takes about 20-30 hours [17, 18].

Once inside the body, dapsone passes into the enterohepatic circulation and is metabolized by the liver. Metabolic inactivation is carried out through cytochrome P450 (CYP) in hepatocytes. However, other cells such as polymorphonuclear cells (PMNs) and monocytes can contribute to its metabolism [19]. Dapsone metabolism can occur in two ways in hepatocytes: N-acetylation (by an N-acetyltransferase) or N-hydroxylation (by isoforms of CYP) such as cytochrome P450-2E1 (CYP2E1) and cytochrome P450-2C (CYP2C).

Acetylation generates Monoacetyldapsone (MADDS) [20, 21] and hydroxylation, dapsone hydroxylamine (DDS-NHOH) [22]. Dapsone is distributed into all organs and excreted through urine and a small amount can be excreted in feces [6].

The bacteriostatic effect is given by the regulation of folic acid synthesis (necessary for DNA synthesis) by inhibiting the enzyme dihydropteroate synthetase that incorporates Paraminobenzoic Acid (PABA) into dihydropteroate, which is the immediate precursor of folic acid [23].

The anti-inflammatory effect on PMNs is carried out by the inhibition of the formation of ROS [24], as well as by the inhibition of Myeloperoxidase (MPO), the enzyme responsible for producing Hypochlorous acid (HOCl), a highly reactive and cytotoxic compound [25, 26]. Dapsone also inhibits the cell migration process (adherence to endothelium and chemotaxis) of PMNs; by interfering with chemokine receptors (G protein-coupled receptors; (GPCRs), integrins (CD11b / CD18) [27-29], chemotaxis by Leukotriene B4 (LTB4) [30] and inhibition of the formation of the Interleukin-8 (IL-8) [31, 32]. Other cytokines also identified as a target for dapsone are Interleukin 1 beta (IL-1β) and Tumor Necrosis Factor-alpha (TNF-α) [33] (Fig. 2).

Dapsone has a well-known safety profile. Adverse effects occur between 0.5-3.6% of people taking dapsone pills for the control of infections [16]. Methemoglobinemia is the main adverse effect of dapsone, and Methemoglobin molecule possesses a high affinity for molecular iron that produces hypoxia by not allowing oxygen release in the tissues [23, 34, 35].

Clinically, hypoxemia manifestations as dyspnea, acrocyanosis, and headache, as well as the presence of hemolysis in laboratory tests, and dissociation between the concentration of oxyhemoglobin in blood and oxygen desaturation using the pulse oximeter characterizes this condition.

Methemoglobinemia and hemolysis, as the adverse effects of dapsone, may coincide with the genetic deficiency of 6-phosphate dehydrogenase, with chronic use of the drug and in some cases with doses higher than 200 mg/kg. A recent study demonstrated the utility of high doses of dapsone in three patients suffering from relapsing and remitting Lyme disease; they were treated with double doses of dapsone (200 mg/kg/day for a total of 7-8 weeks) showed remission of main Lyme symptoms for a period of 25 to 30 months with no side effects [36]. Furthermore, it is relevant to note that these adverse effects are reversible as medication stops [37-39], and some treatments, such as methylene blue and ascorbic acid, are available to resolve clinical methemoglobinemia [40].

3.1. Epilepsy and Status Epilepticus

Epilepsy is one of the most common neurological problems, affecting 1% to 2% of the human world population. The International League Against Epilepsy (ILAE) defined epilepsy as a chronic neurological condition characterized by recurrent epileptic seizures. A seizure is a brain dysfunction with transitory paroxysms with a recurrent tendency and spontaneous termination [41]. Some works report that temporal lobe epilepsy in humans and animal models is associated with neuronal loss in the hippocampus during epileptogenesis [42, 43]. On the other hand, status epilepticus (SE) is a severe medical condition defined by the ILAE as a disorder that results from the failure of the mechanisms responsible for the termination or the initiation mechanisms of the crisis, which leads to abnormal and prolonged seizures: It is a condition frequently related with long-term consequences including neuronal death, neuronal damage, and disruption of neural networks, depending on the type and duration of seizures [44].

Regardless of the presence or not of any systemic, cardiovascular, or metabolic complication as well as pre-existing epilepsy, SE produces disseminated neuronal loss and reactive gliosis in the hippocampus, amygdala, the dorsomedial nucleus of the thalamus, in the cerebellar Purkinje cell layer, and the periamigdaloid (piriformis) region.

In patients with SE, the neuronal loss has a similar distribution to that seen in SE induced by domoic acid intoxication in humans and SE induced by Kainic acid and pilocarpine in rats [45].

There is a wide variety of medications used to treat epilepsy. These include sodium, potassium, and calcium transmembrane blockers, N-methyl-D-aspartate (NMDA) α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) channel blockers, gamma-amino butyric acid (GABA) agonists or enhancers, and synaptic vesicle blockers, all of which improved over time, resulting in a new generation of antiepileptic drugs. The therapeutic success of antiepileptic drugs depends on the tolerability of the drug, adherence to treatment and the reduction of adverse reactions (dizziness, headache, diplopia, and ataxia) [46] as well, in some cases, of the capacity to develop treatment resistance [47]. Most of these drugs have little or no neuroprotective effect; therefore, it seems reasonable to propose new therapeutic strategies with an alternative, complementary and neuroprotective approach with minimal adverse reactions even with prolonged use with not drug resistance (Fig. 2).

Recent work shows the efficacy of dapsone to treat epilepsy and SE in animals and humans (Table 1) [48-58]. In support of the above, some authors describe that the acute and chronic administration of dapsone (6.25, 9.375, 12.5 mg/kg) reduces the number of seizures generated by electrical stimulation of the amygdala and hippocampus in cats with no adverse reactions (maximum dose of 40 mg/kg) [48, 49]. On the other hand, the use of dapsone (9,375 and 125 mg/kg) administered 30 min before inducing seizures by kainic acid (AK) (10 mg/kg) decreases the number of seizures and mortality in a dose-dependent manner in rats [50]. Likewise, the use of dapsone and sodium phenobarbital (12.5/30 mg/kg, respectively) alone or in combination diminished KA-induced seizures, decreased lipoperoxidation, and significantly increases neuronal hippocampal viability in rats [51]. Similarly, the combination of dapsone and Diazepam (25/20 mg/kg, respectively) administered during seizures demonstrated therapeutic efficacy in a model of SE induced by KA by significantly reducing the electrical activity associated with this condition; this effect remained up to 24 hours after drugs administration.

A more significant number of viable hippocampal CA-3 pyramidal neurons were also found in animals treated with dapsone than in the control group (untreated). This study indicates that dapsone is not only an anticonvulsant drug but also a neuroprotective one [52]. Dapsone analogs have also been shown to have a neuroprotector effect by decreasing lipoperoxidation, increasing cell viability, preventing GABA reduction, and improving behavioral disturbances, after the application of quinolinic acid, a known agonist of the NMDA receptor. Some of those analogs, with N- substituents, also decreased methemoglobin levels compared to dapsone itself [53, 54] (Fig. 2).

A clinical study shows the therapeutic effect of dapsone in patients who develop resistance to conventional treatments. Administration of 100 mg/day decreased the frequency of seizures per month by more than 50%, after a follow-up for 3 months. In terms of therapeutic safety, there were no severe adverse effects related to dapsone daily administration. Only symptoms such as methemoglobinemia (at subclinical levels), headaches, drowsiness, and paleness were observed [55]. The studies carried out on the anticonvulsant effect of dapsone in vivo models, and one study in drug-resistant epileptic patients have shown encouraging results to consider dapsone and some of its analogs, a potential treatment to decrease the number and intensity of seizures and the consequent degeneration of nervous tissue, necessary for preserving CNS functions.

3.2. Parkinson's Disease

PD is a progressive neurodegenerative disorder characterized by the massive loss of dopaminergic neurons in the Substantia Nigra pars compacta (SNc) [59] and the generalized presence of intracytoplasmic and intraneuritic inclusions of α aggregates-synuclein (Lewy bodies (DLB)), and Lewy Neurites (LN) [60]. PD results from the interaction between genetic susceptibility and some identified environmental factors [61]. After AD, PD is the second most common chronic and systemic neurodegenerative disease in adults [62, 63].

In industrialized countries, the prevalence of this disease ranges between 0.3% and 1% in older than 60 years and reaches 3% in those older than 80 years or more, with incidence rates that vary between 0.08 and 0.18 per 1,000 people/year [64]. The main clinical characteristics of patients with PD are impairments in motor functions such as tremor at rest, rigidity, postural instability, and bradykinesia. It also causes non-motor manifestations, including cognitive, behavioral and pain [65]. Several studies have reported that motor and non-motor problems are related to aging, accelerating neuronal dysfunction, and extended loss of dopaminergic neurons in the SNc. Several studies have reported that motor and non-motor problems are related to aging, accelerating neuronal dysfunction, and extended loss of dopaminergic neurons in the SNc.

Disturbance of protein degradation by the ubiquitin-proteasome system might have a critical role in neurodegeneration. Parkin is a ubiquitin-protein ligase involved in protein degradation as collaborating with the ubiquitinconjugating enzyme UbcH7. PD patients show loss of this ubiquitin-protein ligase activity [66, 67].

Interestingly, long-term treatment with dapsone (2 mg/kg) restores parkin levels through its up-regulation. Furthermore, chronic treatment with dapsone prevents neuronal loss related to normal aging and reduces oxidative stress in mice with MPTP-induced PD [68].

On the other hand, a study on cellular aging, using an animal aging and lifespan model in worms (C. elegans) treated with paraquat (free radical-generating compound, used as a model of Parkinson´s disease), dapsone (5 mg/kg) reduces the production of free radicals and increased life expectancy and motor activity [69].

3.3. Dementia and Alzheimer's Disease

Dementia is a state of progressive cognitive impairment that leads to loss of independent functions and significant disruption of daily living activities [70]. More than 70 conditions cause the clinical syndrome of dementia [71]. Of these, AD represents 60-80% of all cases, followed by vascular dementia and other neurodegenerative dementias such as DLB dementia, dementia-Parkinson complex, and frontotemporal dementia [72]. Around 35.6 million people worldwide are affected by AD, mainly affecting people over 65 [73]. Therefore, AD should be suspected in a patient older than 60 years who suffers from cognitive impairment and progressive short-term memory impairment. Although AD definitive diagnosis requires a histopathological or post-mortem study [74], biological markers are now available to make an early diagnosis. Among these, quantification of total Tau protein (Tau), Phosphorylated Tau isoforms (P-Tau181 and P-Tau231), and β-amyloid peptide (Ab42), in cerebrospinal fluid, showed sensitivity and specificity of 80-90% [75].

Drugs used to treat AD, and other forms of degenerative dementia can resolve biochemical abnormalities due to neuronal loss but do not modify the underlying neuropathology or its progression. Cholinesterase inhibitors partially restore the acetylcholine deficiency that arises from the loss of neurons in the nucleus basalis of Meynert and the central septum area, projecting to the cortical regions. Memantine as an NMDA receptor inhibitor eventually attenuates the toxic effects of glutamate released by degenerating neurons, although its exact mechanism of action is uncertain. No drug has shown neuroprotective potential in humans [76].

Chronic inflammatory processes are related to the progression of different degenerative diseases, including AD. There is evidence that dapsone treatment by regulating brain cells' inflation decreases the progression of cognitive disorders in patients with AD [71]. A clinical study demonstrated that leprosy patients treated with dapsone had a lower incidence of dementia than tuberculosis treatment [77] and without treatment [78]. Dapsone does not seem to have a direct effect on the degenerative neuronal process once it shows high levels of β-amyloid in cell cultures and patients with AD [79, 80]; therefore, it is possible that dapsone does not modify the progression of the disease in advanced phases. However, a recent review [81] suggests that it is necessary to develop a combined drug therapy to attenuate chronic inflammation and confer neuroprotection in AD. In this report, it is proposed that the mechanisms to neuroprotect against AD must include: anti-inflammatory actions, show drug permeability through the Blood-Brain Barrier (BBB), evidence of an efficacy in blocking oxidative damage and the chemotactic response mediated by activated microglia; Evidence indicates that dapsone possesses these effects in different conditions both in clinical and experimental studies, and this strategy could be used to delay the progression of AD (Fig. 3).

Given these data, it is important to consider of interest to carry out new research to determine if the anti-inflammatory effect of dapsone is useful or not to modify the course of the disease.

3.4. Cognitive Dysfunction and Depression

Yang et al. (2017) [82] evaluated the effect of propofol on cognition in aged rats treated or not with dapsone, since this anesthetic commonly produces postoperative cognitive dysfunction in elderly patients. The results showed that propofol produces alterations in learning and memory in rats, associated with decreased autophagy in the hippocampus and that pretreatment with dapsone at a dose of 5 mg / kg or 10 mg / kg of body weight significantly improved the behavioral disorder and positively regulated the inhibited autophagic response.

Propofol is frequently related to postoperative cognitive dysfunction in elderly patients. Yang et al. (2017) [82] evaluated propofol's effect on cognition in aged rats treated or not with dapsone. They confirmed that propofol produces alterations in learning and memory in rats, associated with decreased autophagy in the hippocampus, and pretreatment with dapsone at a dose of 5 mg / kg or 10 mg / kg of body weight significantly improved the behavioral disorder and positively regulated the inhibited autophagic response.

Dapsone has also been proposed as an antidepressant treatment in experimental models of aged mice undergoing abdominal surgery since it has been described that depression induced by surgical stress and anxiety are common complications in patients after surgery, as well as recent studies have shown that oxidative stress is involved in the pathophysiology of depression and anxiety induced by surgical stress [83]. As dapsone is known to possess antioxidant properties, Zhang et al. (2015) [84] evaluated the effect of dapsone on depressive and anxious behavior and brain oxidative stress in a surgical stress model. The results demonstrated depressive and anxiety-like behaviors accompanied by elevated brain oxidative stress in aged mice undergoing abdominal surgery and that pretreatment with dapsone 5 mg / kg significantly improved the mice's behavior and decreased brain oxidative stress. They also observed that surgical stress increased the level of NADPH oxidase in the brain, while pretreatment with dapsone blocked the elevation of NADPH oxidase triggered by surgical stress. Therefore, the authors suggest that dapsone is effective in preventing oxidative damage to the brain induced by surgical stress by downregulating the level of NADPH oxidase in elderly mice.

Furthermore, because depression induced by surgical stress and anxiety are common complications in patients after surgery, dapsone has also been proposed as an antidepressant treatment in experimental models of aged mice undergoing abdominal surgery.

Recent studies have shown that oxidative stress is involved in the pathophysiology of depression and anxiety induced by surgical stress [83]. As dapsone is known to possess antioxidant properties, Zhang et al. (2015) [84] evaluated the effect of dapsone on depressive and anxious behavior and brain oxidative stress in a surgical stress model. The results demonstrated depressive and anxiety-like behaviors accompanied by elevated brain oxidative stress in aged mice undergoing abdominal surgery and that pretreatment with dapsone 5 mg/kg has a significant improvement on the mice behavior and decreased brain oxidative stress. They also observed that surgical stress increased NADPH oxidase's level in the brain, while pretreatment with dapsone blocked the elevation of NADPH oxidase triggered by surgical stress. Therefore, the authors suggest that dapsone effectively prevents oxidative damage to the brain induced by surgical stress by downregulating the level of NADPH oxidase in elderly mice.

3.5. Multiple Sclerosis and Other Autoimmune Diseases

Multiple Sclerosis (MS) is a chronic inflammatory disorder of the CNS characterized by demyelination and axonal and neuronal degeneration [85]. MS affects more than 2 million people worldwide [86], presenting itself as the most common cause of non-traumatic disability in young adults [87]. The most common symptoms include visual loss in one eye due to optic neuritis, limb weakness, sensory dysfunction due to transverse myelitis, double vision due to brain stem dysfunction, or ataxia due to cerebellar injury. These lesions occur throughout the white matter of CNS as focal areas of demyelination, inflammation, and glial reaction [86]. Activation of the inflammasome and the breakdown of the BBB seems to ​​play fundamental roles in the autoimmune and pro-inflammatory responses in various neurological diseases, including MS and autoimmune encephalitis, since the excessive induction of Caspase-1 (Cas-1) leads to a programmed cell death process called pyroptosis characterized by the rapid induction of an inflammatory response leading to cell lysis [88]. As mentioned previously, MS is a demyelinating disease of the CNS and remains the most common autoimmune disorder affecting the CNS [86]. Although the cause of MS remains unclear, the pathological mechanisms present can be due to damage to myelin-producing cells (oligodendrocytes) or direct damage to the myelin layer by autoimmune T cells. Recent advances have indicated that inflammasomes contribute to the etiology of MS [89]. In this way, inflammasomes are multiprotein complexes of the innate immune response involved in the processing of Cas-1, the activation of the pro-inflammatory cytokines IL-1β and IL-18, as well as the mechanism of pyroptosis mediated by cell death and activation of the adaptive immune response [90]. Inhibition of the inflammasome is a therapeutic strategy used in patients with MS. Interferon- β (IFNβ) is one of the first-line treatments for MS and can inhibit the inflammasomes NLRP1 and NLRP3 [91]. Based on this information, dapsone may be useful in patients with MS since it can covalently compete with proteins that activate the NLRP3 inflammasome and to decrease the nuclear factor -kappa B (NF-kB) signaling that drives transcription of inflammatory cytokines and chemokines, including IL-1β, IL-18, and IL-8, and priming the expression of NLRP3 to its functional level [71]. On the other hand, the BBB rupture contributes to the development of the disease because the autoaggressive T cells cross this barrier, causing demyelination that eventually leads to progressive disability [92]. The BBB integrity maintenance represents a fundamental pillar for the correct functioning of the CNS; some misfunctioning of this barrier are associated with various neurodegenerative diseases [93, 94]. The BBB has high selective permeability to peripheral molecules and cells, which allows maintaining CNS homeostasis [95]. Endothelial Cells (EC) are the hallmark of this barrier. Specific proteins in the CE of the CNS allow tight junctions between the BBB cells, preventing a possible leakage of molecules or cells potentially damaging to the tissue. These proteins are claudins, occludins, and Zonula Occludens (ZO) cytoplasmic proteins [96, 97]. An experimental study using a model of disruption of BBB in rats by administering lipopolysaccharide demonstrated that the administration of 0.5 mg/kg, 2 mg/kg and 5 mg/kg of dapsone managed to normalize the BBB in a dose-dependent effect by regulating the levels of the Zonula occludens-1 (ZO-1), occludin and claudin-5, which are responsible for generating the tight junctions of the BBB [98]. In another similar study, dapsone induced recovery of the BBB integrity in a model of injury generated by a high-fat diet in mice. The continuous administration of dapsone reversed the lipid peroxidation induced by this diet and the loss of tight junction proteins after eight weeks [99].

Dapsone is a proven effective treatment for subacute cutaneous lupus erythematosus, particularly in refractory drug cases [100]. The potential mechanisms for this efficacy are attributed to the inhibition of the myeloperoxidase enzyme by dapsone, its inhibitory effect on the synthesis and release of prostaglandins, the inhibition of the production of leukotrienes C4 and the inhibition of the adherence of neutrophils to cells vascular endothelial cells and their subsequent extravasation through the endothelial vascular wall, thus preventing the migration of neutrophils to the injury sites [101].

Furthermore, dapsone has been tested to treat bullous systemic lupus erythematosus, a rare bullous condition associated with systemic lupus erythematosus [102]. The results showed that dapsone was effective in 90% of the cases to diminished dermal infiltration of polynuclear neutrophils, alignment of these cells at the basal membrane zone and leukocytoclastic. Therefore, the authors conclude that dapsone is the first-choice option for this disease.

Finally, the therapeutic efficacy of dapsone has been tested in autoimmune diseases such as pemphigus and pemphigoid, two variants of the autoimmune mucocutaneous bullous dermatoses [103]. The anti-inflammatory action of dapsone lies in its ability to suppress neutrophils migration and production of toxic secretory products that cause skin damage [6, 28]. Therefore, it is effective in various skin disorders associated with abnormal neutrophils accumulation such as dermatitis herpetiformis, linear IgA bullous dermatosis, pyoderma gangrenosum, PV, BP, sweet’s syndrome and vasculitis [5, 6]. All the patients showed a satisfactory response to dapsone, achieving disease remission in a short period with no serious side-effects necessitating treatment cessation.

3.6. Dapsone in Ischemic and Traumatic Diseases of the Central Nervous System

3.7. Cancer

Cancer is an anormal and uncontrolled cellular growth in any organ or body structure [126]. Current cancer research focuses on early recognition of a malignant lesion delimiting the patient's healthy tissue and implementing radio and medical therapy. The knowledge of the tumor microenvironment allows for describing and predicting cancer cells' behavior and response to a specific treatment. This microenvironment is composed of fibroblasts, immune cells, cells that form new blood vessels, and the proteins produced by all cells present in the tumor that promote the growth of cancer cells [127].

In Glioblastoma (GB), the tumoral CE abnormally generates IL-8 and increases neutrophil recruitment. Neutrophils, in turn, produce Vascular Endothelial Growth Factor (VEGF), inducing angiogenesis and more CE that produce more IL-8 and greater recruitment of neutrophils as a vicious circle [128, 129]. This accumulation of neutrophils in the tumor tissue is a biological marker of poor prognosis [130, 131].

It has been suggested [132] that dapsone is potentially useful for the treatment of GB multiforme by inhibiting neutrophil accumulation, migration, and response to IL-8, as well as the production of IL-8, [133]. Furthermore, dapsone and its analogs have an antiproliferative effect in glioma cell cultures [134].

3.8. Dapsone as Cytoprotective Drug