Pharmacokinetic considerations need to be taken into account for drugs targeting the central nervous system (CNS). For this reason, in the present chapter, the general pharmacokinetic considerations are described. The CNS comprises the brain and the spinal cord. Both structures are surrounded by a highly selective barrier that protects them, the blood-brain barrier (BBB). However, the permeability of the BBB can be modified in several pathological conditions. To reach the CNS, the free form of the drug must be able to cross the BBB and achieve adequate concentrations, which can be a challenge. Characteristics to consider include the drug’s lipid solubility, active transport mechanisms, such as P-glycoprotein, and protein binding. These factors will influence the absorption, distribution, metabolism, and elimination (ADME) properties of the drug, as well as its ability to cross the BBB. To enhance brain penetration, in addition to systemic methods for administering drugs that target the CNS, the development of delivery systems that enhance the transport of drugs to the brain has emerged as a promising approach for overcoming the challenges of transport across the BBB. Among these methods, the nose-to-brain route has demonstrated effectiveness, then gained considerable interest recently. Finally, in vitro assays to assess the BBB permeability are briefly described. Understanding these factors is essential for optimizing drug delivery, achieving the desired therapeutic effect, and minimizing potential toxicities.

The treatment of metabolic syndrome (MS), characterized by type 2 diabetes, obesity, dyslipidemias, and cardiovascular problems, requires integral treatment. In addition to its central activity, serotonin also has peripheral effects, implying regulation of blood glucose and insulin levels. Indorenate is a serotonin analog with antihypertensive properties and possible activity on the metabolism of carbohydrates. However, its effect on glucose levels has not been explored, which is relevant in searching for the indorenate’s potential as an alternative to treatment of MS. This investigation aimed to study the effects of indorenate on glycemia through in vivo and in silico assays. In normal rats, indorenate was co-administrated with two serotoninergic antagonists: pelanserin (5-HT2a antagonist) and WAY-100635 (5-HT1a antagonist). Indorenate caused a hypoglycemic effect in normal rats. Pelanserin and WAY-100635 inhibited this effect. In diabetic rats, indorenate increased insulin levels. In addition, indorenate decreased glycemia in an euglycemic clamp test, while pelanserin inhibited this effect. In silico, indorenate exhibited a higher affinity and interactions than serotonin for 5-HT2a and 5HT1a receptors. The data suggest that the hypoglycemic effect of indorenate requires the participation of the 5-HT2a receptor and partially of the 5-HT1a receptor. Finding drugs with beneficial multimodal effects for blood pressure and glycemic control, such as indorenate, might be relevant for treating MS and its associated pathologies.

Adipogenesis is crucial for maintaining energy homeostasis, as it facilitates the differentiation of mesenchymal stem cells into adipocytes. This process is transcriptionally regulated by key factors including PPARγ and C/EBPβ, alongside FABP4 during lipogenesis. However, it is now well established that a significant portion of this regulation is also mediated by small non-coding RNAs (miRNAs) and long non-coding RNAs (lncRNAs), which post-transcriptionally modulate gene expression. This study aimed to identify key miRNAs involved in adipogenesis and to determine how Aloe-emodin, a molecule with potent anti-inflammatory properties known to modulate adipocyte differentiation, alters their expression. Using an integrative approach combining 3T3-L1 cell culture, RNA-seq, and qPCR analyses, this study demonstrates that Aloe-emodin can upregulate transcription factors (PPARγ and C/EBPβ) as well as miR-143 and miR-155, suggesting its potential as a modulator of adipogenic gene or miRNA expression in this exploratory setting.