CHALLENGES OF ALZHEIMER’S TREATMENT
All drugs which entered clinical trials against Alzheimer’s disease failed because their effects were limited to an individual biological pathway, protein or enzyme. They fell into the category of the current paradigm “one gene, one target, one drug”.
However, Alzheimer’s disease is characterized by not only multiple targets but also multiple factors involving physiological, biochemical mediators, leading to cognitive and memory impairment and neuronal death.
The development of an effective multi-target directed drug could represent a new paradigm in the treatment of Alzheimer’s disease or other neurodegenerative diseases.
Our aim is to develop novel drug candidates and solutions to address unmet medical needs. Our molecule Q134R exerts its neuroprotective and cognitive restoration effects at multiple levels. It prevents neuronal death along with astrocyte- and microglia-induced neuroinflammation, decreases amyloid- and tau-related pathological reactions, and restores memory impairment caused by scopolamine or Abeta oligomers. This makes Q134R a novel and a potential disease modifying drug candidate against Alzheimer’s disease and other degenerative diseases of the brain.
Successful completion of the preclinical studies reflects that our Q134R molecule may have a revolutionary role in the fight against Alzheimer’s disease, the most common form of dementia.
Q134R – A UNIQUE COMBINATION OF PATHWAYS
Considering the innate complexity of the pathological conditions of the brain of patients with Alzheimer’s disease (AD), the research process was based on a multiple target approach that could yield the most efficient drugs.
Q134R exerts its positive effects on Alzheimer’s disease in 3 mechanisms of action:
Q134R is a strong cytoprotective agent. At nanomolar concentration, it protects neuronal cells against neuronal death induced by reactive oxygen species (ROS) and Abeta (amyloid beta) oligomers, as well as restores mitochondrial functioning. In cellular assays Q134R induces the expression of genes whose protein products combat oxidative-stress, such as hemoxygenase-1 (HMOX-1), gluthatione peroxidase-1 (GPX-1), superoxide dismutase-1 (SOD-1) and erythropoietin (EPO) in a concentration dependent manner.
Q134R has inhibitory effects on NFATs, a family of calcineurin- (CN) dependent transcription factors linked to multiple pathologic hallmarks that emerge during Alzheimer’s disease. Q134R inhibits both the induction of the NFAT transcriptional activity and caspase-3 enzyme activity, therefore prevents neuronal death by dual effects. Numerous studies show that inhibition of CN/NFAT signalling leads to beneficial effects on amyloid pathology, neuroinflammation, neuronal viability, synaptic physiology, and cognitive function in mouse models of Alzheimer’s disease. Q134R exhibits NFAT inhibitory properties without suppressing direct calcineurin activation, hence no immunosuppressive side-effects are anticipated.
Q134R restores memory impairment caused by scopolamine or Abeta oligomers, by modulation of the GABAA-gated Cl- channels, specific for neuronal cells including those playing a role in extrasynaptic signalling that modulates memory functions.