Rifampicin and Its Derivative Rifampicin Quinone Reduce Microglial Inflammatory Responses and Neurodegeneration Induced In Vitro by α-Synuclein Fibrillary Aggregates

Wang

et al. 2019

Front. Cell. Neurosci.

Mounting evidence suggests that neuroinflammation is not just a consequence but a vital contributor to the development and progression of Parkinson’s disease (PD). Microglia in particular, may contribute to the induction and modulation of inflammation in PD. Upon stimulation, microglia convert into activated phenotypes, which exist along a dynamic continuum and bear different immune properties depending on the disease stage and severity. Activated microglia release various factors involved in neuroinflammation, such as cytokines, chemokines, growth factors, reactive oxygen species (ROS), reactive nitrogen species (RNS), and prostaglandins (PGs). Further, activated microglia interact with other cell types (e.g., neurons, astrocytes and mast cells) and are closely associated with α-synuclein (α-syn) pathophysiology and iron homeostasis disturbance. Taken together, microglial activation and microglia-mediated inflammatory responses play essential roles in the pathogenesis of PD and elucidation of the complexity and imbalance of microglial activation may shed light on novel therapeutic approaches for PD.

Section: Potentials Of Microglia As a Therapeutic Target For Pdmentioning

confidence: 99%

Pharmacological Targeting of Microglial Activation: New Therapeutic Approach

Wang

et al. 2019

Front. Cell. Neurosci.

“…Rifampicin, another antibiotic known to exert multiple neuroprotective functions is suggested as potential treatment regime for PD [ 241 , 242 ]. Rifampicin and its derivative rifampicin quinone were found to reduce microglial inflammatory responses and neurodegeneration induced in vitro by α-Syn fibrillary aggregates [ 243 ]. Rifampicin might also reduce the cytotoxicity by promoting SUMOylation of α-Syn [ 244 ].…”

Section: Therapeutic Possibilities and Pharmaceutical Interventionmentioning

confidence: 99%

Iron Dysregulation and Inflammagens Related to Oral and Gut Health Are Central to the Development of Parkinson’s Disease

et al. 2020

Neuronal lesions in Parkinson’s disease (PD) are commonly associated with α-synuclein (α-Syn)-induced cell damage that are present both in the central and peripheral nervous systems of patients, with the enteric nervous system also being especially vulnerable. Here, we bring together evidence that the development and presence of PD depends on specific sets of interlinking factors that include neuroinflammation, systemic inflammation, α-Syn-induced cell damage, vascular dysfunction, iron dysregulation, and gut and periodontal dysbiosis. We argue that there is significant evidence that bacterial inflammagens fuel this systemic inflammation, and might be central to the development of PD. We also discuss the processes whereby bacterial inflammagens may be involved in causing nucleation of proteins, including of α-Syn. Lastly, we review evidence that iron chelation, pre-and probiotics, as well as antibiotics and faecal transplant treatment might be valuable treatments in PD. A most important consideration, however, is that these therapeutic options need to be validated and tested in randomized controlled clinical trials. However, targeting underlying mechanisms of PD, including gut dysbiosis and iron toxicity, have potentially opened up possibilities of a wide variety of novel treatments, which may relieve the characteristic motor and nonmotor deficits of PD, and may even slow the progression and/or accompanying gut-related conditions of the disease.

“…Pathological forms of α-synuclein, which are spread in the parenchymal tissue of the brain, can contribute to the disease process by stimulating inflammatory-type reactions through microglial cells (38). In one study, by using pure microglial cell culture, the inflammatory potential of three different forms of α-synuclein was tested and TNF-α and IL-6 release as inflammation markers were examined (39). As a result, a fibril form of α-synuclein was found to be the most inflammatory form of protein.…”

Section: Rifampicin α-Synuclein Aggregation and Sumoylation α-Synucmentioning

confidence: 99%

“…Rifampicin and its oxidized derivative, RifQ, have been shown to inhibit the activation of primary microglial cells induced by α-synuclein fibrils, which are inflammatory factors in PD (39,57). RifQ has been shown to have the potential to inhibit neurotoxic effects induced by microglial cells activated by α-synuclein fibrils.…”

Section: Rifampicin (Rif) and Its Oxidated Product (Rifq)mentioning

confidence: 99%

The Effects of Rifampicin on Neuronal Survival

Yurtsever¹,

Emekli-Alturfan²

2020

Experimed

Neurodegenerative diseases are characterized by the formation of insoluble aggregates of misfolded proteins in the central nervous system. The β-amyloid protein in Alzheimer's disease and α-synuclein formation in Parkinson's disease (PD) may be given as examples. In addition to α-synuclein accumulation in Parkinson's disease, mechanisms such as oxidative stress, dysfunction of mitochondria, inflammation response, and apoptosis are known to be involved in the disease process. Since the mechanisms underlying these diseases are partially known, the drugs developed are intended to slow the disease process rather than cure them. Rifampicin is an antibiotic commonly used in humans and known to easily penetrate into the brain after oral intake. Studies have shown that rifampicin suppresses mitochondrial oxidative stress, eliminates α-synuclein fibrils and inhibits inflammation in in vitro and in vivo disease models. In this study, we reviewed recent studies on the neuronal protection of rifampicin and the effects of rifampicin on the pathophysiological mechanisms of PD.