Dendrimers are highly branched macromolecules with the potential to be used for biomedical applications. Several dendrimers are toxic owing to their positively charged surfaces. However, this toxicity can be reduced by coating these peripheral cationic groups with carbohydrate residues. In this study, the toxicity of three types of 4th generation poly (propyleneimine) dendrimers were investigated in vivo; uncoated (PPI-g4) dendrimers, and dendrimers in which 25% or 100% of surface amino groups were coated with maltotriose (PPI-g4-25%m or PPI-g4-100%m), were administered to Wistar rats. Body weight, food and water consumption, and urine excretion were monitored daily. Blood was collected to investigate biochemical and hematological parameters, and the general condition and behavior of the animals were analyzed. Unmodified PPI dendrimers caused changes in the behavior of rats, a decrease in food and water consumption, and lower body weight gain. In the case of PPI-g4 and PPI-g4-25%m dendrimers, disturbances in urine and hematological and biochemical profiles returned to normal during the recovery period. PPI-g4-100%m was harmless to rats. The PPI dendrimers demonstrated dose- and sugar-modification-degree dependent toxicity. A higher dose of uncoated PPI dendrimers caused toxicity, but surface modification almost completely abolished this toxic effect.

HIGHLIGHTS• ASS234 is a MTDL compound containing a moiety from Donepezil and the propargyl group from the PF 9601N, a potent and selective MAO B inhibitor. This compound is the most advanced anti-Alzheimer agent for preclinical studies identified in our laboratory.• Derived from ASS234 both multipotent donepezil-indolyl (MTDL-1) and donepezil-pyridyl hybrids (MTDL-2) were designed and evaluated as inhibitors of AChE/BuChE and both MAO isoforms. MTDL-2 showed more high affinity toward the four enzymes than MTDL-1.• MTDL-3 and MTDL-4, were designed containing the N-benzylpiperidinium moiety from Donepezil, a metal-chelating 8-hydroxyquinoline group and linked to a N-propargyl core and they were pharmacologically evaluated.• The presence of the cyano group in MTDL-3, enhanced binding to AChE, BuChE and MAO A. It showed antioxidant behavior and it was able to strongly complex Cu(II), Zn(II) and Fe(III).• MTDL-4 showed higher affinity toward AChE, BuChE.• MTDL-3 exhibited good brain penetration capacity (ADMET) and less toxicity than Donepezil. Memory deficits in scopolamine-lesioned animals were restored by MTDL-3.• MTDL-3 particularly emerged as a ligand showing remarkable potential benefits for its use in AD therapy.Alzheimer's disease (AD), the most common form of adult onset dementia, is an age-related neurodegenerative disorder characterized by progressive memory loss, decline in language skills, and other cognitive impairments. Although its etiology is not completely known, several factors including deficits of acetylcholine, β-amyloid deposits, τ-protein phosphorylation, oxidative stress, and neuroinflammation are considered to play significant roles in the pathophysiology of this disease. For a long time, AD patients have been treated with acetylcholinesterase inhibitors such as donepezil (Aricept ® ) but with limited therapeutic success. This might be due to the Unzeta et al.New MTDLs for Alzheimer's Disease complex multifactorial nature of AD, a fact that has prompted the design of new MultiTarget-Directed Ligands (MTDL) based on the "one molecule, multiple targets" paradigm. Thus, in this context, different series of novel multifunctional molecules with antioxidant, anti-amyloid, anti-inflammatory, and metal-chelating properties able to interact with multiple enzymes of therapeutic interest in AD pathology including acetylcholinesterase, butyrylcholinesterase, and monoamine oxidases A and B have been designed and assessed biologically. This review describes the multiple targets, the design rationale and an in-house MTDL library, bearing the N-benzylpiperidine motif present in donepezil, linked to different heterocyclic ring systems (indole, pyridine, or 8-hydroxyquinoline) with special emphasis on compound ASS234, an N-propargylindole derivative. The description of the in vitro biological properties of the compounds and discussion of the corresponding structure-activity-relationships allows us to highlight new issues for the identification of more efficient MTDL for use in AD therapy.

A large body of experimental and clinical evidence has strongly suggested that monoamines play an important role in regulating epileptogenesis, seizure susceptibility, convulsions, and comorbid psychiatric disorders commonly seen in people with epilepsy (PWE). However, neither the relative significance of individual monoamines nor their interaction has yet been fully clarified due to the complexity of these neurotransmitter systems. In addition, epilepsy is diverse, with many different seizure types and epilepsy syndromes, and the role played by monoamines may vary from one condition to another. In this review, we will focus on the role of serotonin, dopamine, noradrenaline, histamine, and melatonin in epilepsy. Recent experimental, clinical, and genetic evidence will be reviewed in consideration of the mutual relationship of monoamines with the other putative neurotransmitters. The complexity of epileptic pathogenesis may explain why the currently available drugs, developed according to the classic drug discovery paradigm of “one-molecule-one-target,” have turned out to be effective only in a percentage of PWE. Although, no antiepileptic drugs currently target specifically monoaminergic systems, multi-target directed ligands acting on different monoaminergic proteins, present on both neurons and glia cells, may represent a new approach in the management of seizures, and their generation as well as comorbid neuropsychiatric disorders.

Chronic liver failure induced by portocaval anastomosis (PCA) in Wistar rats resulted in a dramatic increase in histamine concentration in hypothalamus and a smaller, but clearly pronounced, elevation in the rest of brain. Between 10 and 120 days following surgery, shunted rats exhibited a histamine level 2.4- to 13-fold higher in hypothalamus and 1.5- to 2.5-fold higher in the rest of brain as compared to their control, sham-operated pairs. There were no significant changes in histamine concentration in the other examined tissues. The increase in brain histamine could not be attributed to the inhibition of its degradation, because activity of histamine N-methyltransferase remained unchanged for at least 40 days. Although the activity of histidine decarboxylase also remained unchanged when measured at a saturating concentration of L-histidine, the increase in histamine content in brain seems to be due to its enhanced synthesis brought about by increased availability of L-histidine in the tissue, as indicated by two to four times higher concentrations of this amino acid in PCA rats.

Histamine is metabolized by several enzymes in vitro and in vivo. The relevance of this metabolism in the mammalian heart in vivo is unclear. However, histamine can exert positive inotropic effects (PIE) and positive chronotropic effects (PCE) in humans via H2-histamine receptors. In transgenic mice (H2-TG) that overexpress the human H2 receptor in cardiomyocytes but not in wild-type littermate mice (WT), histamine induced PIE and PCE in isolated left or right atrial preparations. These H2-TG were used to investigate the putative relevance of histamine degrading enzymes in the mammalian heart. Histidine, the precursor of histamine, increased force of contraction (FOC) in human atrial preparations. Moreover, histamine increased the phosphorylation state of phospholamban in human atrium. Here, we could detect histidine decarboxylase (HDC) and histamine itself in cardiomyocytes of mouse hearts. Moreover, our data indicate that histamine is subject to degradation in the mammalian heart. Inhibition of the histamine metabolizing enzymes diamine oxidase (DAO) and monoamine oxidase (MAO) shifted the concentration response curves for the PIE in H2-TG atria to the left. Moreover, activity of histamine metabolizing enzymes was present in mouse cardiac samples as well as in human atrial samples. Thus, drugs used for other indication (e.g. antidepressants) can alter histamine levels in the heart. Our results deepen our understanding of the physiological role of histamine in the mouse and human heart. Our findings might be clinically relevant because we show enzyme targets for drugs to modify the beating rate and force of the human heart.