Two drugs have been found that have a protective effect on the brain and are already safely used in people. Prof Giovanna Mallucci, from the MRC Toxicology Unit in Leicester, wants to start human clinical trials on dementia patients soon and expects to know whether the drugs work within two to three years.
When a virus hijacks a brain cell it leads to a build-up of viral proteins.
Cells respond by shutting down nearly all protein production in order to halt the virus’s spread.
Many neurodegenerative diseases involve the production of faulty proteins that activate the same defenses, but with more severe consequences.
The brain cells shut down production for so long that they eventually starve themselves to death.
This process, repeated in neurons throughout the brain, can destroy movement, memory or even kill, depending on the disease.
It is thought to take place in many forms of neurodegeneration, so safely disrupting it could treat a wide range of diseases.
In the initial study, the researchers used a compound that prevented the defence mechanism kicking in.
It halted the progress of prion disease in mice – the first time any neurodegenerative disease had been halted in any animal.
Signalling through the PERK/eIF2α-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer’s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2α-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2α-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2α-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2α-P-mediated translational attenuation in vitro and in vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.
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