The intranasal administration of drugs has been shown to be safer and improves cognitive function in mice models of dementia – more specifically, those with Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies – compared to traditional antibiotics.

A research group from the Department of Translational Neuroscience, Osaka City University Graduate School of Medicine, explained that dementia occurs when proteins called amyloid-β, tau, and α-synuclein accumulate in the brain and form oligomers. Oligomers are responsible for the neuronal dysfunction associated with the clinical features of Alzheimer’s disease and dementia.

The researchers had previously shown in a study using mice that the antibiotic rifampicin removes oligomers from the brain and improves cognitive function. However, the drug has been associated with side effects such as liver damage.

To combat these negative side effects, the researchers decided to combine rifampicin with resveratrol, a naturally occurring antioxidant in plants, in this study: a fixed dose combination of rifampicin and resveratrol was administered intranasally to mice models of Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies. Their cognitive functions and brain pathology was observed five days a week for a total of four weeks.

The results showed that the combination significantly improved the cognitive function of the mice, inhibited the accumulation of oligomers, and restored synaptophysin levels — presynaptic proteins that facilitate synapses.

Meanwhile, blood levels of liver enzymes, a marker of hepatic damage that normally increases with rifampicin, remained normal in the fixed-dose combination; at the same time, increased levels of brain-derived neurotrophic factor (BDNF) expression were observed in the hippocampus, which was not seen with rifampicin alone. These results indicate that this fixed-dose combination is superior to rifampicin alone in terms of both safety and efficacy.

Furthermore, 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 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 – 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,” said Specially Appointed Lecturer Tomohiro Umeda, Osaka City University.

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 development of a fixed-dose combination of rifampicin and resveratrol nasal spray is currently being carried out by Medilabo RFP, a venture company originating from the research team’s laboratory.

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