rifampin and Neurodegenerative-Diseases

There is growing evidence that certain antibiotics exert their beneficial effects not only by killing or inhibiting the growth of bacterial pathogens but also indirectly by immunomodulation. This review aims at giving an overview of the immunomodulatory properties of antibiotics in different diseases: The antiinflammatory properties of macrolides in chronic inflammatory pulmonary disorders were recognized more than 15 years ago and have been well documented in the last decade. Recent data suggest that several antibiotics such as tetracyclines and cephalosporins may have a beneficial immunomodulatory or neuroprotective effect on neuroimmunological and neurodegenerative diseases including multiple sclerosis and amyotrophic lateral sclerosis. Moreover, the non-bacteriolytic but bactericidal antibiotics rifampicin, clindamycin and aminoglycosides kill bacteria without releasing high quantities of proinflammtory cell wall components. The use of bactericidal, non-bacteriolytic protein synthesis inhibitors reduces mortality and long-term sequelae in experimental bacterial sepsis, plague and meningitis. Clinically, macrolides have been well established as an adjunctive treatment to beta-lactam antibiotics in pulmonary diseases. For other indications, appropriate clinical trials are necessary before using the immunomodulatory properties of antibiotics in clinical practice.

Topics: Anti-Bacterial Agents; Fluoroquinolones; Humans; Immunologic Factors; Lung Diseases; Macrolides; Neurodegenerative Diseases; Protein Synthesis Inhibitors; Rifampin; Tetracyclines

Among the mechanisms underlying Parkinson's disease, many pathogenic mechanisms are suggested to be effective such as oxidative stress, mitochondrial dysfunction, disruption of the ubiquitin-proteasome system, and neuroinflammation. Calcium is very important for neuronal and glial cells, neurodegenerative disease mechanisms are closely related to disturbed calcium homeostasis. Recent studies strongly support the role of inflammation in nigrostriatal degeneration in PD. In recent years, Rifampicin, a macrocyclic antibiotic has been shown to have a protective effect on neurons. This study aims to evaluate the effects of rifampicin in the experimental PD model induced by rotenone in zebrafish focusing on the relationship between calcium-dependent mitochondrial dysfunction and inflammation. Adult zebrafish were exposed to rotenone and rifampicin for 3 weeks. Locomotor activity was determined as the total distance that the zebrafish traveled for 5 min. Neuroinflammation and PD-related gene expressions were determined by RT-PCR. Mitochondrial calcium levels were determined using inductively coupled plasma-optical emission spectrometry (ICP-OES). Gamma synuclein, Park 7, Sigma-1 receptor expressions were determined by Western Blot. Our results show that rifampicin may be effective in reducing neuroinflammation, which may be an effective strategy to reduce mitochondrial dysfunction due to impaired calcium homeostasis in PD.

Topics: Animals; Calcium; Homeostasis; Inflammation; Mitochondria; Neurodegenerative Diseases; Neuroinflammatory Diseases; Oxidative Stress; Rifampin; Rotenone; Zebrafish

Aberrant microglial responses promote neuroinflammation in neurodegenerative diseases. However, rifampicin's effect on cognitive and motor sequelae of inflammation remains unknown. Therefore, we investigated whether rifampicin exerts neuroprotection against lipopolysaccharide (LPS)-induced cognitive and motor impairments.. A mouse model of LPS-induced cognitive and motor impairment was established. Adult C57BL/6 mice were injected intraperitoneally with 25 mg/kg rifampicin 30 min before intraperitoneal microinjection of LPS (750 μg/kg) daily until study end. Treatments and behavioral experiments were performed once daily for 7 days. Behavioral tests and pathological/biochemical assays were performed to evaluate LPS-induced damage to the hippocampus and substantia nigra (SN).. Rifampicin protects against LPS-induced neuroinflammation and attenuates cognitive and motor impairments by inhibiting the TLR4/MyD88/NF-κB signaling pathway. Our findings might aid the development of novel therapies to treat progressive neurodegenerative diseases.

Topics: Animals; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Inflammation; Inflammation Mediators; Lipopolysaccharides; Male; Mice; Mice, Inbred C57BL; Microglia; Motor Disorders; Myeloid Differentiation Factor 88; Neurodegenerative Diseases; Neuroprotection; NF-kappa B; Rifampin; Signal Transduction; Substantia Nigra; Toll-Like Receptor 4

Topics: alpha-Synuclein; Cytokines; Humans; Inflammation Mediators; Microglia; Models, Biological; Molecular Structure; Neurodegenerative Diseases; Neurons; Phosphatidylinositol 3-Kinases; Receptors, Purinergic P2X7; Rifampin; Signal Transduction; Toll-Like Receptor 2

Microglial activation plays an important role in the pathophysiology of neurodegenerative diseases, and suppression of microglial activation prevents the progression of neurodegeneration. Rifampicin, a bacteriocidal antibiotic, induces immunosuppression. We hypothesized that rifampicin might be neuroprotective by inhibiting the production of pro-inflammatory mediators, thereby suppressing microglial activation. In the present study, we examined the effects of rifampicin on the production of lipopolysaccharide (LPS)-induced pro-inflammatory mediators and their signaling pathways in BV2 microglia. We also assessed the neuroprotective effects of rifampicin using a co-culture of microglia and neurons. Our results showed that rifampicin inhibited the LPS-stimulated expression of inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis factor-α, and interleukin-1β, as well as the production of nitric oxide and prostaglandin E₂. Moreover, rifampicin suppressed LPS-induced nuclear factor-kappa B activation by blocking the degradation of the inhibitor of the nuclear transcription factor NF-kappa B. Rifampicin inhibited the phosphorylation of mitogen activated protein kinases, although protein kinase B was not inhibited. Preincubation of microglia with rifampicin reduced neurotoxicity and improved neuron survival in a microglia-neuronal co-culture system. Taken together, these findings suggest that rifampicin, with its anti-inflammatory properties, might be a novel treatment for neurodegenerative diseases.

Topics: Animals; Animals, Newborn; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Transformed; Cell Survival; Cells, Cultured; Coculture Techniques; Inflammation; Inflammation Mediators; Mice; Microglia; Neurodegenerative Diseases; Neurons; Rats; Rats, Sprague-Dawley; Rifampin

Rifampicin is an antibacterial drug which is highly effective in the treatment of tuberculosis and leprosy. It has been shown to exert antioxidative as well as anti-apoptotic effects. In this study, the neuroprotective effect of rifampicin was examined after 1-methyl-4-phenylpyridinium (MPP+)-induced dopaminergic cell death in vitro, and on the survival of retinal ganglion cells after optic nerve transection in vivo. Rifampicin administration significantly increased the number of surviving dopaminergic neurons after MPP+ intoxication as compared to control cultures. No cytotoxic effects were noted even at final rifampicin concentrations of 100 microM. In the rifampicin-treated group, retinal ganglion cell survival was significantly increased after axotomy as compared with vehicle-treated and phosphate-buffered saline-treated control animals. These results suggest that rifampicin is able to prevent neuronal degeneration in cell death paradigms involving oxidative stress and activation of apoptotic pathways. It may thus play a role in the future treatments of neurodegenerative disorders.

Topics: 1-Methyl-4-phenylpyridinium; Animals; Cell Count; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Interactions; Embryo, Mammalian; Enzyme Inhibitors; Immunohistochemistry; In Vitro Techniques; Male; Mesencephalon; Mice; Mice, Inbred C57BL; Neurodegenerative Diseases; Neurons; Optic Nerve Injuries; Rats; Rats, Wistar; Retinal Ganglion Cells; Rifampin; Tyrosine 3-Monooxygenase