Judith Espinosa-Raya

Inhibition of acetylcholinesterase by two arylderivatives: 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione and cis-N-p-Acetoxy-phenylisomaleimide

Two arylderivatives, 3a-Acetoxy-5H-pyrrolo(1,2-a) (3,1)benzoxazin-1,5-(3aH)-dione 3 and cis-N-p-Acetoxy-phenylisomaleimide 4, were synthesized from anthranilic acid and para-aminophenol, respectively. The inhibitory effects of these compounds on acetylcholinesterase (AChE) activity were evaluated in vitro as well as by docking simulations. Both compounds showed inhibition of AChE activity (Ki = 4.72 ± 2.3 μM for 3 and 3.6 ± 1.8 μM for 4) in in vitro studies. Moreover, they behaved as irreversible inhibitors and made π–π interaction with W84 and hydrogen bonded with S200 and Y337 according to experimental data and docking calculations. The docking calculations showed ΔG bind (kcal/mol) of − 9.22 for 3 and − 8.58 for 4. These two compounds that can be use as leads for a new family of anti-Alzheimer disease drugs.

Short- and long-term treatment with estradiol or progesterone modifies the expression of GFAP, MAP2 and Tau in prefrontal cortex and hippocampus

AIMS We analyzed the effects of the short- and long-term administration of estradiol (E2) or progesterone (P4) after ovariectomy on the expression of MAP2, Tau and GFAP in prefrontal cortex and hippocampus. MAIN METHODS Sprague Dawley rats were ovariectomized and immediately treated with E2 or P4 for 2 or 18 weeks. At the end of treatments, hippocampus and prefrontal cortex were excised, proteins were extracted and MAP2, Tau and GFAP were analyzed by Western blot. KEY FINDINGS MAP2 and Tau content was not modified by E2 in the prefrontal cortex. On the contrary, P4 decreased MAP2 content after a short-term treatment, while it increased that of MAP2 and TAU in this brain region after a long-term treatment. E2 increased MAP2 content in hippocampus. In this region, short-term administration of P4 increased that of MAP2. GFAP content was diminished after a long-term administration of P4 in hippocampus. SIGNIFICANCE Current data emphasize the importance of short- and long-term sex steroid treatment on neuronal and glial cytoskeletal proteins expression.

Chronic administration of tibolone modulates anxiety-like behavior and enhances cognitive performance in ovariectomized rats

Hormone replacement therapy (HRT) may be prescribed to prevent the symptoms of menopause. This therapy may include estrogenic and/or progestin components and may increase the incidence of endometrial and breast cancers. Tibolone (TIB), which is also made up of estrogen and progestin components, is often used to reduce the impact of HRT. However, the effect of TIB on the processes of learning, memory and anxiety has yet to be fully elucidated. The aim of this study was to evaluate the long-term effect on learning, memory processes and anxiety in ovariectomized rats caused by different doses of TIB (0 mg/kg, 0.01 mg/kg, 0.1 mg/kg 1.0 mg/kg and 10 mg/kg, administered daily via the oral route for 18 weeks). Two behavioral animal models, the autoshaping and T maze models were employed. The concentrations of acetyl choline transferase (ChAT) and tryptophan hydroxylase (TPH) in the hippocampus were directly measured by Western blot. No significant changes were observed in the autoshaping model and spontaneous activity test. In the T maze, increased latency was observed with TIB doses of 1 and 10 mg/kg compared to the vehicle. We observed that the ChAT content decreased with increasing doses of TIB, whereas TPH content increased with doses of 1 and 10 mg/kg of TIB. These data indicate that high doses of TIB improved emotional learning, which may be related to the modulation of the cholinergic and serotonergic systems by TIB.

Effect of a M1 Allosteric Modulator on Scopolamine-Induced Amnesia

It is well accepted that acetylcholine is involved in memory and learning processes and that loss of memory is characteristic of Alzheimers disease (AD). Several muscarinic agonists have been shown to be clinically effective in the treatment of AD. However, their use has been limited due to adverse side effects. As a result, more selective M1 agonists are expected to be the next generation of agents for the treatment of AD. One pharmacological approach to evaluate possible cognitive effects of compounds includes their ability to reverse scopolamine-induced amnesia. In the current study the succinamide and succinimide of p-aminophenol, two newly synthesized compounds that were previously designed to be acetylcholine analogues, were evaluated in a Pavlovian/Instrumental autoshaped memory task. Simultaneously, docking studies on the M1 receptor were done. The scopolamine-induced amnesia was reversed by the amide but not the imide. These findings are in line with results derived from the docking simulations, and suggest that at least the succinamide of p-aminophenol could represent a novel candidate for the treatment of AD.

Tibolone modulates neuronal plasticity through regulating Tau, GSK3β/Akt/PI3K pathway and CDK5 p35/p25 complexes in the hippocampus of aged male mice.

Aging is a key risk factor for cognitive decline and age-related neurodegenerative disorders. Also, an age-related decrease in sex steroid hormones may have a negative impact on the formation of neurofibrillary tangles (NFTs); these hormones can regulate Tau phosphorylation and the principal kinase GSK3β involved in this process. Hormone replacement therapy decreases NFTs, but it increases the risk of some types of cancer. However, other synthetic hormones such as tibolone (TIB) have been used for hormone replacement therapy. The aim of this work was to evaluate the long-term effects of TIB (0.01 mg/kg and 1 mg/kg, intragastrically for 12 weeks) on the content of total and hyperphosphorylated Tau (PHF-1) proteins and the regulation of GSK3β/Akt/PI3K pathway and CDK5/p35/p25 complexes in the hippocampus of aged male mice. We observed that the content of PHF-1 decreased with TIB administration. In contrast, no changes were observed in the active form of GSK3β or PI3K. TIB decreased the expression of the total and phosphorylated form of Akt while increased that of p110 and p85. The content of CDK5 was differentially modified with TIB: it was increased at low doses and decreased at high doses. When we analyzed the content of CDK5 activators, an increase was found on p35; however, the content of p25 decreased with administration of low dose of TIB. Our results suggest a possible mechanism of action of TIB in the hippocampus of aged male mice. Through the regulation of Tau and GSK3β/Akt/PI3K pathway, and CDK5/p35/p25 complexes, TIB may modulate neuronal plasticity and regulate learning and memory processes.

Design (Docking and QSAR Studies) and synthesis of histone deacetylase 2 (HDAC2) inhibitors series

In recent years, it has been shown that histone deacetylase 2 (HDAC2) inhibitors increase histone acetylation and enhance memory processes, probably due to an increase in the gene transcription rate that emerges during memory formation. Histone acetylation generally favors long-term memory, whereas histone deacetylation impinges on it. However, until today there is no specific drug that can target the HDAC2 active site. In this work we applied the method of rational drug design, through enzyme-structural-chemical properties to generate new molecules as HDAC inhibitors. By the application of Quantitative Structure-Activity Relationship (QSAR) and molecular modeling methodologies our aim is to predict more potent HDAC inhibitors. 76 small molecules with potential activity were analyzed using QSAR methodology. The best model was constructed by merging the properties of electronegativity, atomic mass, polarizability, van der Waals forces and some conformational aspects, with the following statistical parameters: r2 = 0.8935, q2LOO-CV = 0.8498, and q2LGO-CV = 0.7598. The molecular docking of the ligands on the template was performed by blind docking. The results showed intermolecular interactions between small molecules and some amino acids, such as His145, His146, Asp179, Asp186, and internal-H2O and Zn2+ of which IN01, IN04, and IN14 showed theoretically better biological activity compared with that of TSA and SAHA. Mainly, the IN14 synthesized molecule is a theoretical inhibitor of HDAC class I.