ABSTRACT
The striatum, an essential component of the brain's motor and reward systems, plays a pivotal role in a wide array of cognitive processes. Its dysfunction is a hallmark of neurodegenerative diseases like Parkinson's disease (PD) and Huntington's disease (HD), leading to profound motor and cognitive deficits. These conditions are often related to excitotoxicity, primarily due to overactivation of NMDA receptors (NMDAR). In the synaptic cleft, glycine transporter type 1 (GlyT1) controls the glycine levels, a NMDAR co-agonist, which modulates NMDAR function. This research explored the neuroprotective potential of NFPS, a GlyT1 inhibitor, in murine models of striatal injury. Employing models of neurotoxicity induced by 6-hydroxydopamine (PD model) and quinolinic acid (HD model), we assessed the effectiveness of NFPS pre-treatment in maintaining the integrity of striatal neurons and averting neuronal degeneration. The results indicated that NFPS pre-treatment conferred significant neuroprotection, reducing neuronal degeneration, protecting dopaminergic neurons, and preserving dendritic spines within the striatum. Additionally, this pre-treatment notably mitigated motor impairments resulting from striatal damage. The study revealed that GlyT1 inhibition led to substantial changes in the ratios of NMDAR subunits GluN2A/GluN1 and GluN2B/GluN1, 24 h after NFPS treatment. These findings underscore the neuroprotective efficacy of GlyT1 inhibition, proposing it as a viable therapeutic strategy for striatum-related damage.
Subject(s)
Glycine Plasma Membrane Transport Proteins , Huntington Disease , Mice , Animals , Glycine Plasma Membrane Transport Proteins/metabolism , Sarcosine/pharmacology , Neuroprotection , Glycine/pharmacology , Corpus Striatum/metabolism , Huntington Disease/drug therapyABSTRACT
A new series of sixteen multifunctional N-benzyl-piperidine-aryl-acylhydrazones hybrid derivatives was synthesized and evaluated for multi-target activities related to Alzheimer's disease (AD). The molecular hybridization approach was based on the combination, in a single molecule, of the pharmacophoric N-benzyl-piperidine subunit of donepezil, the substituted hydroxy-piperidine fragment of the AChE inhibitor LASSBio-767, and an acylhydrazone linker, a privileged structure present in a number of synthetic aryl- and aryl-acylhydrazone derivatives with significant AChE and anti-inflammatory activities. Among them, compounds 4c, 4d, 4g and 4j presented the best AChE inhibitory activities, but only compounds 4c and 4g exhibited concurrent anti-inflammatory activity in vitro and in vivo, against amyloid beta oligomer (AßO) induced neuroinflammation. Compound 4c also showed the best in vitro and in vivo neuroprotective effects against AßO-induced neurodegeneration. In addition, compound 4c showed a similar binding mode to donepezil in both acetylated and free forms of AChE enzyme in molecular docking studies and did not show relevant toxic effects on in vitro and in vivo assays, with good predicted ADME parameters in silico. Overall, all these results highlighted compound 4c as a promising and innovative multi-target drug prototype candidate for AD treatment.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cholinesterase Inhibitors/pharmacology , Drug Discovery , Hydrazones/pharmacology , Indans/pharmacology , Neuroprotective Agents/pharmacology , Piperidines/pharmacology , Acetylcholinesterase/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Donepezil , Dose-Response Relationship, Drug , Hep G2 Cells , Humans , Hydrazones/chemistry , Indans/chemical synthesis , Indans/chemistry , Models, Molecular , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Piperidines/chemical synthesis , Piperidines/chemistry , Structure-Activity RelationshipABSTRACT
Minocycline is a tetracyclic antibiotic whose non-antibacterial activities, including anti-inflammatory, antinociceptive, and neuroprotective effects, have been widely studied. Thus, a better understanding of the mechanisms underlying its pleiotropic activities is important. Primary microglial cell cultures were established from cerebral cortices of 1-day neonatal Wistar rats. Minocycline (3-100 µM) or its vehicle was added to the culture media 30 min prior to 24 h incubation with lipopolysaccharide (LPS; 10 ng/mL). Cell viability after these treatments was assessed by ATP-based luminescence test. Prostaglandin (PG) E(2) and 8-iso-PGF(2α) were determined by enzyme immunoassays. Cyclooxygenase-2 and microsomal PGE(2) synthase-1 protein levels were measured by western blot analysis. First, it was shown that minocycline (30 or 100 µM) inhibits PGE(2) production in LPS-activated primary rat microglial cells. Then, by investigating targets involved in this inhibition, it was found that minocycline (3-100 µM) inhibits microsomal PGE(2) synthase-1, but not cyclooxygenase-2, expression. Additionally, minocycline (3-100 µM) inhibited the production of 8-iso-PGF(2α). This study warrants the conduction of in vivo studies to evaluate the pharmacological relevance of these findings.
