Neurodegenerative diseases (NDs) are a group of chronic, progressive, disabling, and incurable diseases, which represent one of the biggest challenges for current research in the fields of medicinal chemistry and health sciences. NDs are a vast group of neuronal disorders that include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) as the most common prevalent forms. The number of individuals with some kind of dementia is estimated from 46.8 million people worldwide in 2015 to nearly 50 million people in 2017. Considering the current increase in the elderly population worldwide, especially in the most developed countries, this number is thought to almost double every 20 years, reaching 75 million in 2030 and 131.5 million in 2050. The etiology of such NDs is still not fully understood, but the elderly, associated with selective neuronal vulnerability, are considered the main risk factor. The biochemical and cellular basis of NDs has been intensively studied during the last two decades, and currently, there is a consensus that their hallmark is represented by complex multifactorial-based pathogenesis, affecting protein misfolding, immune system activation, mitochondrial dysfunction, oxidative stress, neuronal loss, and neuroinflammation. In the brain defense system, microglial cells act as macrophage-like cells, monitoring and regulating tissue homeostasis in the neuronal environment, and play a key role in neuroinflammatory conditions related to NDs. During their regulatory functions in brain homeostasis, these cells can undergo changes in their metabolism and morphology, leading to two types, named resting and activated microglia. Resting microglia may turn into other distinct phenotypes depending on the signals received and could originate an M1 state, that releases pro-inflammatory cytokines and other cytotoxic substances, which activate astrocytes and reinforce inflammation and neurodegeneration. Once activated, microglia produce proinflammatory and neurotoxic factors, including cytokines such as TNF-α, interleukin-1 beta (IL-1β), IL-6, and free radicals (e.g., NO, superoxide) as a response to immunological stimuli. Therefore, in the last decades, a number of results have demonstrated that inflammation around misfolding protein deposits leads to the destruction of neighboring neurons, being also responsible, at least in part, for an exacerbated oxidative condition, increasing the generation of radical species that, in turn, modify the intracellular environment and reinforce neuroinflammation. Thus, considering the lack of efficacy from the current available one-target selective drugs for the treatment of NDs, and that neuroinflammation is one of the key factors of onset and progression of NDs, the development of multi-target directed ligands, which include anti-neuroinflammatory properties, could represent a great advance in the development of more effective and disease-modifying drug candidates for NDs.

Keywords: neuroinflammation; neurodegenerative diseases; multi-target directed ligands; neuroprotection; multifunctional drug candidates; drug design for neurodegenerative diseases