• Nasal spray containing rifampicin and resveratrol significantly improved mouse cognition.
  • This nasally administered mixture reduced toxic proteins that drive neurodegeneration.

How can you treat a disease before symptoms show? This puzzle has stymied researchers and pharmaceutical companies developing preventative treatments (prophylactics) for neurodegenerative dementia. One thing is to address the problem conceptually — a drug with efficient brain and cell entry that provides sufficient clinical effects at a low dose, risk, and cost; it’s quite another to find a practical, real-world solution. 

Researchers from Osaka City University developed an intranasally administrable mixture that preserves mouse cognition and blocks toxic protein aggregation in several models of neurodegenerative disease. In a study published in Frontiers in Neuroscience, Umeda and colleagues paired a drug called rifampicin that can prevent neurodegeneration but has toxic side effects with resveratrol — an anti-oxidant and anti-inflammatory with neuroprotective effects.  Their results show the advantages of this combinatorial medicine regarding safety and effectiveness over single-drug rifampicin, providing a feasible means to prevent neurodegenerative dementia that targets toxic proteins.

(Credit: Takami Tomiyama) Rifampicin and resveratrol have the potential as an anti-dementia combinatorial drug. Combining the generic drug rifampicin and the dietary supplement resveratrol administered with a nasal spray enables a safer and more effective preventative measure against dementia. 

Neurodegenerative Dementia Prevention with Intranasal Rifampicin and Resveratrol

Based on recent findings from clinical trials, a consensus has been established that the treatment of neurodegenerative dementia should be started earlier from the asymptomatic stages before the brain degenerates. That means, to prevent dementia, medicines need to be made that are cost-effective, safe, easily administered, and brain-penetrant, all while targeting multiple toxic proteins that trigger neurodegeneration — a tall order.

To fulfill these requirements, Umeda and colleagues combined two neuroprotective compounds, rifampicin and resveratrol. Rifampicin is now an inexpensive generic drug, and resveratrol is also cheap, meaning the combinatorial medicine can be produced and provided at a low cost. This pairing aims to create a safe and effective mixture that prevents neurodegenerative dementia by targeting toxic proteins.

(Umeda et al., 2021 | Frontiers in Neuroscience) Effects of intranasal rifampicin and resveratrol combination on neurodegeneration causing toxic proteins. When looking at the levels of toxic proteins (yellowish staining) that cause neurodegeneration in the cortex (CTX) and hippocampus (HC), the levels are high in the Alzheimer’s mice treated with a control solution (Tg + CMC). Although treatment with rifampicin (RFP) or resveratrol (Resv) alone reduced the intensity of this staining significantly, the combinatorial treatment (RFP + Resv) was even more potent. These data are shown in images on the top two rows, which are quantified in the bottom two graphs.

Regarding the administration, although oral administration is the easiest option, oral rifampicin can cause adverse events, and oral resveratrol is quickly metabolized into inactive forms. Nasal sprays also allow patients to easily and non-invasively take these drugs, which is why the Osaka City University researchers chose the nose-to-brain route for their administration. The intranasal combination of the two drugs can overcome these problems and even shows several advantages over single-drug treatment.

Both drugs have been shown to have antioxidant and anti-inflammatory properties while preventing toxic protein accumulation that triggers neurodegeneration. Still, several problems have been observed when either is used alone. Rifampicin is an antibiotic whose adverse effects are well recognized. It occasionally induces liver injury and drug-drug interaction.

Umeda and colleagues proposed that resveratrol, a very safe and widely used as a dietary supplement, can antagonize these rifampicin actions.

“To combat the negative side effects of the existing drug rifampicin, we thought of combining it with the hepatoprotective effects of resveratrol,” states Professor Takami Tomiyama, the senior author and lead investigator for the current study.

As predicted, when these two drugs were combined, the rifampicin-induced liver toxicity vanished, indicating that resveratrol acts on the liver cells (hepatocytes) protectively and neutralizes rifampicin’s toxicity, as we expected.

Finally, regarding bioavailability in the brain and broad targeting of toxic proteins, the Osaka City University researchers showed that the intranasal administration cleared several neurodegeneration-causing toxic proteins, including amyloid-beta and tau. These results suggest that intranasal rifampicin and resveratrol penetrate the brain and cells. The combination of rifampicin and resveratrol also rescued cognition and oligomer-related pathologies in these mouse models. 

(Umeda et al., 2021 | Frontiers in Neuroscience) Effects of intranasal rifampicin and resveratrol combination on memory Alzheimer’s mice. A solution containing 0.02 mg of either rifampicin (RFP) or resveratrol (Resv) alone or in combination (RFP + Resv) were intranasally administered every day into 15-month-old Alzheimer’s mice for one month. In the Morris water maze test, the combinatorial medicine significantly improved mouse memory to levels of non-Alzheimer’s littermates (Non-Tg + CMC), as shown by the amount of time it took for the mice to find the escape platform (left plot) and the time spent in the quadrant containing the escape platform (right plot).

What’s Next for the Rifampicin-Resveratrol Drug Combo?

There have already been several clinical trials examining rifampicin and resveratrol separately. For example, a clinical trial with oral rifampicin and an antibiotic called doxycycline was performed for mild to moderate Alzheimer’s disease that did not benefit cognition or function. Also, clinical trials with oral resveratrol for mild to moderate Alzheimer’s disease did not have significant clinical outcomes. These results do not necessarily indicate the ineffectiveness of either drug.

Umeda and colleagues argue that the main reason for these failures is the late timing of the medication. To support this, the Osaka City University research team discusses a 2017 retrospective study in non-demented patients treated with rifampicin for mycobacterium infections indicated that oral rifampicin effectively prevents Alzheimer’s disease but requires a dose of at least 450 mg daily for one year. So, they claim that If the treatment is started before the neurodegeneration and the drug is administered intranasally, rifampicin and resveratrol might effectively prevent Alzheimer’s disease.

Furthermore, based on the team’s previous research experience, they know how the dosage information in mice transfers to humans. Umeda and colleagues state that 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 20 g.

“Converted to a human dosage based on body surface area, it becomes 0.081 mg/kg/day,” states senior author 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.”

Further investigation is necessary to determine the appropriate ratio of the two drugs and how best to prepare the mixture for intranasal administration in patients. Studies examining the safety and toxicity of intranasally administered drugs are also required. However, since rifampicin and resveratrol are widely used and well-known pharmaceutical and dietary supplements, respectively, Umeda and colleagues expect that the development of this combinatorial medicine in people should not be too challenging, which merits their drug repositioning.