Studies by scientists at Osaka City University Graduate School of Medicine suggest that intranasal delivery of the generic antibiotic drug rifampicin, in combination with the dietary supplement resveratrol, could represent a feasible approach to preventing neurodegenerative disorders, such as Alzheimer’s disease. Their newly reported research showed that a five-day course of treatment with the drug combination improved cognitive function and inhibited the accumulation of oligomers in the brains of four different mouse models of neurodegenerative dementia, including Alzheimer’s disease.
Research lead Takami Tomiyama, PhD, and colleagues, reported on their findings in Frontiers in Neuroscience, in a paper titled, “Oligomer-Targeting Prevention of Neurodegenerative Dementia by Intranasal Rifampicin and Resveratrol Combination—A Preclinical Study in Model Mice,” in which they concluded, “Our findings provide a feasible means for the prevention of neurodegenerative dementia by targeting toxic oligomers.”
Neurodegenerative dementias include Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Parkinson’s disease (PD) can also result in dementia when it spreads into the brain’s cerebral cortex, the authors explained. These disorders are characterized by accumulation in the brain of disease-specific amyloidogenic proteins: Aß and tau in AD, tau or TDP-43 in FTD, and α-synuclein in DLB and PD,” the team continued. Such proteins tend to self-aggregate into characteristic Aß plaques, neurofibrillary tangles of hyperphosphorylated tau, and Lewy bodies of phosphorylated α-synuclein, which can be useful for the differential diagnosis of neurodegenerative diseases. However, the investigators pointed out, “… accumulating evidence indicates that the real causal culprit of the disease is smaller, soluble oligomers of the proteins.”
And despite the “vigorous efforts” of researchers and pharma companies, there is no effective cure for neurodegenerative dementia. “Many drug candidates have been developed, but most have failed to show beneficial effects on patients’ cognition in clinical trials.” This failure is possibly due to two primary reasons, the late timing of medication, and the wrong drug target, the authors believe. “The treatment should be started early, before the neurodegeneration proceeds, and the drug target should be set to the toxic oligomers,” they stated.
The newly reported study builds on the team’s previous experiments in mice, which found that the generic antibiotic rifampicin removed oligomers from the brain and improved cognitive function. “We previously demonstrated that a well-known antibiotic, rifampicin, inhibited the oligomerization of Aß, tau, and α-synuclein in vitro and that the activity was specific to pathological amyloidogenic proteins but not to physiologically assembling proteins …These results suggest that rifampicin is a promising oligomer-targeting medicine and can prevent neurodegenerative dementia when administered early before the neurodegeneration,” the scientists stated.
However, oral use rifampicin has been associated with side effects such as liver damage, and with drug-drug interactions. Such adverse events are thought to occur during the first pass of rifampicin from the intestine to the liver. To avoid this pathway the researchers looked to an alternative, intranasal delivery route for rifampicin, which results in less transport to the liver, but efficiently delivers the drug to the brain through the nasal mucosa epithelium.
The team also wanted to identify potential compounds that might help to secure the long-term safety of nasal rifampicin delivery. “… we explored the literature for a compound that possesses hepatoprotective actions opposite to rifampicin and, if possible, additional clinical effects that rifampicin does not show,” they explained. “We consequently selected trans-resveratrol as a candidate.”
Resveratrol is a naturally occurring antioxidant in plants, and is used widely as a dietary supplement. Studies have also indicated that the compound has anti-inflammatory, anti-diabetic, anti-cancer and neuroprotective effects, and demonstrates activity that might neutralize the hepatotoxicity and drug-drug interactions of rifampicin, the authors noted. As Tomiyama commented, “To combat the negative side effects of the existing drug rifampicin, we thought of combining it with the hepatoprotective effects of resveratrol.”
For their newly reported studies, the research group administered a fixed dose combination of rifampicin and resveratrol intranasally, five days a week for a total of four weeks, to mice models of Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies. The results demonstrated that the drug combination improved cognitive function and brain pathology. Combination therapy inhibited the accumulation of oligomers, and restored synaptophysin levels—presynaptic proteins that facilitate synapses. “Compared with rifampicin and resveratrol alone, the combinatorial medicine significantly improved mouse cognition, reduced amyloid oligomer accumulation, and recovered synaptophysin levels in the hippocampus.… the combination showed a synergistic effect in ameliorating mouse cognition,” the researchers pointed out.
Furthermore, increased levels of brain-derived neurotrophic factor (BDNF) expression were observed in the hippocampus, which was not seen with rifampicin alone. “BDNF plays an important role in synaptic formation and contributes to memory function,” the scientists stated. Additionally, blood levels of liver enzymes, a marker of hepatic damage that normally increases with rifampicin, remained normal in mice given the fixed-dose combination. These results indicated that the fixed-dose combination is superior to rifampicin alone in terms of both safety and efficacy.
Based on the team’s previous research experience, nasal administration of a fixed dose combination of rifampicin and resveratrol would increase drug transferability to the brain and further enhance both safety and medicinal effects. The dosage used in this study was 0.02 mg of rifampicin per mouse per day, or 1 mg/kg/day assuming a mouse weight of 20g. “Converted to a human dosage based on body surface area, it becomes 0.081 mg/kg/day,” states Prof. Tomiyama, “currently, rifampicin is prescribed at 10 mg/kg/day as an antibiotic, and compared to this, we confirmed an effect at a much lower dosage.”
Encouragingly, both drugs are also inexpensive. “ … rifampicin is now an inexpensive generic drug, and resveratrol is also cheap,” the team pointed out. “Thus, the combinatorial medicine could be provided at low cost.”
“The number of patients with dementia has been increasing all over the world, with some sources predicting a doubling of patients every 20 years. However, there is still no effective treatment for the disease,” stated Specially Appointed Lecturer Tomohiro Umeda, PhD, first author of the study. “Recent studies have shown that abnormalities begin to appear in the brains of dementia patients more than 20 years before the onset of the disease.” By investigating new therapeutic purposes with existing drugs in a process called drug repositioning, the research team hopes to diagnose and prevent dementia before the neurons start dying.”
The authors acknowledged that further studies will be needed to determine the appropriate ratio of the two drugs, along with pharmacokinetic and general toxicity studies. Nevertheless, they pointed out, “ … since rifampicin and resveratrol are widely used and well-known pharmaceutical and dietary supplements, respectively, we expect that the development of the combinatorial medicine should not be too challenging, which merits their drug repositioning.”
Development of a fixed-dose combination of rifampicin and resveratrol nasal spray is currently being carried out by Medilabo RFP, a venture company spun out from the research team’s laboratory. The company is preparing for global clinical trials. Medilabo RFP established a US subsidiary, in Massachusetts, in November 2021, with support from the Japan External Trade Organization (JETRO).