Ladostigil

Alzheimer's disease (AD) is a chronic, age-related, and irreversible brain disorder that typically develops slowly and gets worse over time. The potent auspicious drug candidate for the treatment of AD is supposed to perform the simultaneous modulation of several targets linked to AD. The new therapeutic approach involves drug candidates that are designed to act on multiple targets and have various pharmacological properties. This trend has triggered the development of various multimodal drugs including TV-3326 (i.e. ladostigil) and M-30 (i.e. a new multitarget iron chelator). TV-3326 combines the neurorestorative/neuroprotective effects of the cholinesterase (ChE) inhibitory activity of rivastigmine with rasagiline (a selective monoamine oxidase-B inhibitor and novel antiparkinsonian agent) in a single molecule. M-30, the second derivative of rasagiline, was developed by combining the propargyl moiety of rasagiline into the skeleton of VK-28 (i.e. a novel brain permeable neuroprotective iron chelator). It has been revealed that both the compounds possess anti-AD effects and therefore, the clinical development is directed to the treatment of this type of neurodegenerative diseases (NDs). In this article, we have reviewed the neuroprotective molecular mechanisms and multimodal effects of TV-3326 and M-30.

Episodic and spatial memory decline in aging and are controlled by the hippocampus, perirhinal, frontal and parietal cortices and the connections between them. Ladostigil, a drug with antioxidant and anti-inflammatory activity, was shown to prevent the loss of episodic and spatial memory in aging rats. To better understand the molecular effects of aging and ladostigil on these brain regions we characterized the changes in gene expression using RNA-sequencing technology in rats aged 6 and 22 months. We found that the changes induced by aging and chronic ladostigil treatment were brain region specific. In the hippocampus, frontal and perirhinal cortex, ladostigil decreased the overexpression of genes regulating calcium homeostasis, ion channels and those adversely affecting synaptic function. In the parietal cortex, ladostigil increased the expression of several genes that provide neurotrophic support, while reducing that of pro-apoptotic genes and those encoding pro-inflammatory cytokines and their receptors. Ladostigil also decreased the expression of axonal growth inhibitors and those impairing mitochondrial function. Together, these actions could explain the protection by ladostigil against age-related memory decline.