Because of the Dementia Management Act in Korea, the Sorokdo National Hospital strengthened the diagnosis of dementia for HD. Since 2010, Korean medical staff have conducted neuropsychiatric examinations and diagnosed patients with AD.
For HD patients, doctors perform standard treatment according to AD diagnosis and test results. They strengthened the prescription of AADs and discontinued DDS in patients with inactive leprosy. As a result, it became possible to separate the group taking DDS from the group not taking DDS in among AD patients. As a long-term study of HD patients living in Sorok Island for 15 years, the relationship between AD and dapsone is clear. If any study reflects populations who have been prescribed and then discontinued to take dapsone in the statistical data, the effects of dapsone as an inflammasome competitor are mixed in the pathology findings4–8.
DDS readily passes through the blood-brain barrier (BBB)
The results of many epidemiologic studies and limited clinical evidence suggest that NSAIDs should delay the onset and hinder AD's progression. The results of long-term clinical trials were negative. Still, these drugs affect the periphery of the inflammatory reaction14. The components of the neurovascular unit harmoniously working influence the BBB's properties. The brain capillary phenotypes have differences in a lack of fenestration and low pinocytotic activity. They mostly have the presence of tight junctions with low permeability between cells. Since most central nervous system (CNS) diseases are caused by inflammation and oxidative stress, the efficiency of drugs acting on CNS is essential15.
Although we cannot completely understand the role of microglia in neurological diseases, we can summarize beneficial or harmful phenomena: beneficial, with the role of microglia as housekeeping phagocytes for maintaining tissue homeostasis, or dangerous, with the role of microglia determining a pro-inflammatory state that results in synaptic dysfunction and elevated secretion of potentially neurotoxic cytokines16. DDS passes through the BBB, and high-dose sulfadiazine results in an effective CSF concentration in humans17.
DDS appears to have more significant anti-inflammatory effects than NSAIDs. Moreover, DDS does not have the side effects of NSAIDs, such as gastrointestinal disorders; therefore, it is possible to administer adequate doses of DDS (100–300 mg/day) while monitoring other side effects.
DDS in neuroinflammatory foci
The NLRP3 inflammasome in the CNS can be activated in both healthy and pathologic states. As developments in the inflammasome field have uncovered molecular mechanisms, inflammasomes contribute to a broad range of neurological disorders. They are associated with specific mutations in inflammasome genes and diseases modulated by inflammasome activators18. NLRP3 inflammasomes are cytosolic protein complexes that initiate inflammatory responses through caspase activation by infectious or host stimuli. When specific NLRP3 inflammasome was inhibited in organotypic cerebellar cultures, it effectively reduced axonal damage in a lipopolysaccharide-induced neuroinflammation model. The roles of IL1B and the NLRP3 inflammasome are crucial as prognostic biomarkers and potential therapeutic targets in patients with primary progressive multiple sclerosis19. The NLRP3 inflammasome in the CNS is the most abundant and is an essential contributor to neuroinflammation in a broad range of neuronal disorders. By the most extensively investigated inflammasome, it is known that the downregulation of inflammasome activity increases phagocytosis in astrocytes by the release of the chemokine CCL3 (C-C motif ligand 3)20.
DDS had anticonvulsive effects in the amygdaloid inflammation model of epilepsy21. DDS prevents neuronal damage induced by glutamate agonists. Usually, glutamate excitotoxicity is implicated in damage after rat brain ischaemia22. DDS suppressed the mRNA expression of TNF-α and significantly decreased the level of TNF‐α in the culture supernatant23. DDS showed a remarkable ability to reduce damage markers through antioxidant, anti-inflammatory, and anti‐apoptotic effects24. DDS restored the parkin level and prevented age-dependent dopaminergic neuronal loss and transcriptionally activated parkin via protein kinase RNA-like endoplasmic reticulum kinase-activating transcription factor 4 (ATF4)25.
DDS is a neuro-inflammasome competitor in AD
Neurotoxicity, aggregation, and free radical formation are initiated by the methionine (Met) residue at position 35 in the Aβ C-terminal domain26,27. Two-electron oxidation of bicarbonate is mediated by hydrogen peroxide after the generation of peroxymonocarbonate (HCO4−). The bicarbonate/carbon dioxide pair stimulated One-electron oxidations. Carbonate radical anions (CO3●ㅡ) mediate one-electron reactions to promote one-electron oxidation to efficiently oxidize thioether sulfur of the Met residue to sulfur radical cations (MetS●+)28. DDS has a structure that can competitively reduce the positively charged sulfur radical production rate because it has a similar structure to methionine sulfoxide.
SERP1 is a γ-secretase activator that stimulates Aβ generation in cells experiencing endoplasmic reticulum (ER) stress, such as diabetes (an inflammatory condition in cells)29. Although low-density lipoprotein receptor-related protein 1 (LRP1) controls the endocytosis and subsequent spread of tau30, it is essential to identify a mechanism that blocks tau production. Considering the structure of DDS and the allosteric regulation of the molecular unit, DDS can be presumed to preserve cells by decreasing neutrophils' inflammatory response.
DDS can regulate the production of hypochlorous acid. This response is associated with myeloperoxidase, a kind of reductase enzyme, and reduces inflammatory reactions10. DDS in the sandwich test disk showed myeloperoxidase-inhibitor activity in the whole saliva from subjects with periodontal disease. AD is associated with heme-bound Aβ peptides' peroxidase activity, affecting neurotransmitters' oxidative degradation, such as serotonin. DDS12 inhibited myeloperoxidase activity.
DDS may regulate NLRP3 inflammasome activators and a common signalling pathway. However, the specific NLRP3 target may act through a competitive therapeutic mechanism to counter the progression of MCI to AD. Our work corroborates a finding reported in 1994: antibodies could inhibit this activation against complement receptors in the nanomolar range. DDS and indomethacin are weakly inhibitory (10− 4 M range) therapeutic agents in AD3.