Do You Remember Mitochondria?

Dementia is one among the consequences of aging, and amnesia is often one of the most common symptoms. The lack of memory, as a consequence of both "healthy" aging or neurodegenerative conditions, such as in Alzheimer's disease, has a dramatic impact on the patient's lifestyle. In fact, the inability to recall information made by a previous experience could not only alter the interaction with the environment, but also lead to a loss of identity. Mitochondria are key regulators of brain's activity; thanks to their "dynamic organelles" nature they constantly rearrange in the cell body and move along axons and dendrites, changing in dimension, shape, and location, accordingly to the cell's energy requirements. Indeed, the energy they can provide is essential to maintain synaptic plasticity and to ensure transmission through presynaptic terminals and postsynaptic spines. Stressful conditions, like the ones found in neurodegenerative diseases, seriously impair mitochondria bioenergetic, leading to both loss of proper neuronal interaction and of neuron themselves. Here, we highlighted the current knowledge about the role of mitochondria and mitochondrial dynamics in relation to neurodegenerative disorders linked to aging. Furthermore, we discuss the obstacles as well as the future perspectives aimed to enlarge our knowledge about mitochondria as target for new therapeutic strategies to slow down aging and neurodegenerative disease's symptoms.

Cyclopenta[d]pyrimidines and dihydropyrrolo[2,3-d]pyrimidines as potent and selective corticotropin-releasing factor 1 receptor antagonists.

Two new classes of potent and selective CRF(1) receptor antagonists are presented. Exploration of general templates 3 and 4 through modifications of the top amine and bottom phenyl substituents led to optimization of the in vitro affinity and pharmacokinetic profiles. The typical alkyl chains present in the top region of CRF(1) antagonists were replaced by substituted heteroaryl moieties, leading to a dramatic improvement of the metabolic stability. This improvement was apparent when the compounds were dosed in vivo: several compounds exhibited low plasma clearance, good oral bioavailability, and high brain penetration. As a consequence of their outstanding pharmacokinetic profiles, these CRF(1) antagonists, as exemplified by compound 4 fi (4-(4-bromo-3-methyl-1H-pyrazol-1-yl)-7-(2,4-dichlorophenyl)-2-methyl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine), produced a dose-dependent "anxiolytic-like" effect when administered orally, decreasing the vocalization of rat pups.