Eunice D. Farfán-García

Effect of natural exogenous antioxidants on aging and on neurodegenerative diseases

Abstract Aging and neurodegenerative diseases share oxidative stress cell damage and depletion of endogenous antioxidants as mechanisms of injury, phenomena that are occurring at different rates in each process. Nevertheless, as the central nervous system (CNS) consists largely of lipids and has a poor catalase activity, a low amount of superoxide dismutase and is rich in iron, its cellular components are damaged easily by overproduction of free radicals in any of these physiological or pathological conditions. Thus, antioxidants are needed to prevent the formation and to oppose the free radicals damage to DNA, lipids, proteins, and other biomolecules. Due to endogenous antioxidant defenses are inadequate to prevent damage completely, different efforts have been undertaken in order to increase the use of natural antioxidants and to develop antioxidants that might ameliorate neural injury by oxidative stress. In this context, natural antioxidants like flavonoids (quercetin, curcumin, luteolin and catechins), magnolol and honokiol are showing to be the efficient inhibitors of the oxidative process and seem to be a better therapeutic option than the traditional ones (vitamins C and E, and β-carotene) in various models of aging and injury in vitro and in vivo conditions. Thus, the goal of the present review is to discuss the molecular basis, mechanisms of action, functions, and targets of flavonoids, magnolol, honokiol and traditional antioxidants with the aim of obtaining better results when they are prescribed on aging and neurodegenerative diseases.

Boron-containing acids: preliminary evaluation of acute toxicity and access to the brain determined by Raman scattering spectroscopy.

Boron-containing compounds (BCCs), particularly boron containing acids (BCAs), have become attractive moieties or molecules in drug development. It has been suggested that when functional groups with boron atoms are added to well-known drugs, the latter are conferred with greater potency and efficacy in relation to their target receptors. However, the use of BCAs in drug development is limited due to the lack of a toxicological profile. Consequently, the aim of the present study was to evaluate the acute toxicity of boric and boronic acids. Thus, a determination was made of the lethal dose (LD50) of test compounds in male CD1 mice, as well as the effective dose required to negatively affect spontaneous motor activity and to produce notable behavioral abnormalities. After treatment of animals at different doses, macroscopic observations were made from a necropsy, and Raman scattering spectroscopic studies were carried out on brain tissue samples. In general, the results show that most of the tested BCAs have very low toxicity, evidenced by the high doses required to induce notable toxic effects (greater than 100 mg/kg of body weight for all compounds, except for 3-thyenilboronic acid). Such toxic effects, presumably mediated by action on the CNS, include eye damage, gastrointestinal effects (e.g., gastric-gut dilatation and fecal retention), sedation, hypnosis and/or trembling. This preliminary toxicological profile suggests that BCAs can be considered potential therapeutic agents or moieties to be added to other compounds in the development of new drugs. Future studies are required to explore possible chronic toxicity of BCCs.

Current data regarding the structure-toxicity relationship of boron-containing compounds.

Boron is ubiquitous in nature, being an essential element of diverse cells. As a result, humans have had contact with boron containing compounds (BCCs) for a long time. During the 20th century, BCCs were developed as antiseptics, antibiotics, cosmetics and insecticides. Boric acid was freely used in the nosocomial environment as an antiseptic and sedative salt, leading to the death of patients and an important discovery about its critical toxicology for humans. Since then the many toxicological studies done in relation to BCCs have helped to establish the proper limits of their use. During the last 15 years, there has been a boom of research on the design and use of new, potent and efficient boron containing drugs, finding that the addition of boron to some known drugs increases their affinity and selectivity. This mini-review summarizes two aspects of BCCs: toxicological data found with experimental models, and the scarce but increasing data about the structure-activity relationship for toxicity and therapeutic use. As is the case with boron-free compounds, the biological activity of BCCs is related to their chemical structure. We discuss the use of new technology to discover potent and efficient BCCs for medicinal therapy by avoiding toxic effects.

Effects of Tibolone on the Central Nervous System: Clinical and Experimental Approaches

Hormone replacement therapy (HRT) increases the risk of endometrial and breast cancer. A strategy to reduce this incidence is the use of tibolone (TIB). The aim of this paper was to address the effects of TIB on the central nervous system (CNS). For the present review, MEDLINE (via PubMed), LILACS (via BIREME), Ovid Global Health, SCOPUS, Scielo, and PsycINFO (ProQuest Research Library) electronic databases were searched for the results of controlled clinical trials on peri- and postmenopausal women published from 1990 to September 2016. Also, this paper reviews experimental studies performed to analyze neuroprotective effects, cognitive deficits, neuroplasticity, oxidative stress, and stroke using TIB. Although there are few studies on the effect of this hormone in the CNS, it has been reported that TIB decreases lipid peroxidation levels and improves memory and learning. TIB has important neuroprotective effects that could prevent the risk of neurodegenerative diseases in postmenopausal women as well as the benefits of HRT in counteracting hot flashes, improving mood, and libido. Some reports have found that TIB delays cognitive impairment in various models of neuronal damage. It also modifies brain plasticity since it acts as an endocrine modulator regulating neurotransmitters, Tau phosphorylation, and decreasing neuronal death. Finally, its antioxidant effects have also been reported in different animal models.

Disruption of motor behavior and injury to the CNS induced by 3-thienylboronic acid in mice.

The scarcity of studies on boron containing compounds (BCC) in the medicinal field is gradually being remedied. Efforts have been made to explore the effects of BCCs due to the properties that boron confers to molecules. Research has shown that the safety of some BCCs is similar to that found for boron-free compounds (judging from the acute toxicological evaluation). However, it has been observed that the administration of 3-thienylboronic acid (3TB) induced motor disruption in CD1 mice. In the current contribution we studied in deeper form the disruption of motor performance produced by the intraperitoneal administration of 3TB in mice from two strains (CD1 and C57BL6). Disruption of motor activity was dependent not only on the dose of 3TB administered, but also on the DMSO concentration in the vehicle. The ability of 3TB to enter the Central Nervous System (CNS) was evidenced by Raman spectroscopy as well as morphological effects on the CNS, such as loss of neurons yielding biased injury to the substantia nigra and striatum at doses ≥200mg/kg, and involving granular cell damage at doses of 400mg/kg but less injury in the motor cortex. Our work acquaints about the use of this compound in drug design, but the interesting profile as neurotoxic agent invite us to study it regarding the damage on the motor system.

Not all boronic acids with a five-membered cycle induce tremor, neuronal damage and decreased dopamine

HIGHLIGHTSWe analyzed the toxicity of boronic acids with five‐membered cycles as substituent.We found different profiles for each tested compound.Three of six boron‐containing compounds produced shaking behavior.Not all tested compounds produced neuronal death in basal nuclei. ABSTRACT Several striatal toxins can be used to induce motor disruption. One example is MPTP (1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine), whose toxicity is accepted as a murine model of parkinsonism. Recently, 3‐Thienylboronic acid (3TB) was found to produce motor disruption and biased neuronal damage to basal ganglia in mice. The aim of this study was to examine the toxic effects of four boronic acids with a close structural relationship to 3TB (all having a five‐membered cycle), as well as boric acid and 3TB. These boron‐containing compounds were compared to MPTP regarding brain access, morphological disruption of the CNS, and behavioral manifestations of such disruption. Data was collected through acute toxicity evaluations, motor behavior tests, necropsies, determination of neuronal survival by immunohistochemistry, Raman spectroscopic analysis of brain tissue, and HPLC measurement of dopamine in substantia nigra and striatum tissue. Each compound showed a distinct profile for motor disruption. For example, motor activity was not disrupted by boric acid, but was decreased by two boronic acids (caused by a sedative effect). 3TB, 2‐Thienyl and 2‐furanyl boronic acid gave rise to shaking behavior. The various manifestations generated by these compounds can be linked, in part, to different levels of dopamine (measured by HPLC) and degrees of neuronal damage in the basal ganglia and cerebellum. Clearly, motor disruption is not induced by all boronic acids with a five‐membered cycle as substituent. Possible explanations are given for the diverse chemico‐morphological changes and degrees of disruption of the motor system, considering the role of boron and the structure‐toxicity relationship.

Differences in brain regions of three mice strains identified by label-free micro-Raman

Abstract The analysis of different central nervous system regions is interesting and necessary as each one is involved in specific physiological processes and pathologies. On that matter, differences in the chemical composition between the same brain regions in different mice strains have been reported. In this sense, the development of a simple method for the identification of these regions depending on their chemical composition becomes relevant. Raman microspectroscopy, a non-destructive analytical chemical approach for biological samples, is a widely used method for qualitative, quantitative, and structural analysis in biochemical research. Ten brain structures in three different mice strains (Triple transgenic for Alzheimer Disease, 3xTgAD; Cluster 57 black 6, C57BL/6; and the Swiss strain, CD1) were analyzed, and variations among samples from several brain regions were found. Particularly, the pattern of signals from the hippocampus, the prefrontal and temporal cortices, the basal forebrain, the striatum, the cerebellum, and the hypothalamus was discernable. Interestingly, notable signals regarding non-peptide small neurotransmitters were observed, including those related to acetylcholine. These bands were present in the Raman spectra of the basal forebrain and prefrontal cortex in the three mice strains, consistent with the relative abundance of this neurotransmitter in those regions. However, signals with lower intensities appeared in the basal forebrain of C57BL/6 in comparison with the same tissue of the other two strains. In addition, the Raman intensity of bands assigned to catecholamines in the striatum was lower in the 3xTgAD than those from both CD1 and C57BL/6 mice strains. This approach, as well as the reported differences, has potential application for designing analysis on specific murine models of brain diseases.

Several effects of boron are induced by uncoupling steroid hormones from their transporters in blood

Boron is increasingly added to food supplements due to multiple effects that have been reported in mammals after boric acid administration. Among these effects are inflammatory process control, bone and muscle strength enhancement, protein expression regulation, and a decreased risk of developing some pathologies in which these processes are key, such as osteoporosis, dermatological inflammatory non-infectious maladies and diseases affecting the central nervous system. Experimental data have suggested that steroid hormone levels in plasma change after boric acid administration, but a clear mechanism behind these variations has not been established. We analyzed possibilities for these changes and hypothesized that boric acid disrupts the interactions between steroid hormones and several carriers in plasma. In particular, we proposed that there is an uncoupling of the interactions between sex hormone binding globulin (SHBG) and estrogens and testosterone and that there are alterations in the binding of hydrophobic ligands by other carrier proteins in plasma. Further experimental and computational studies are required to support the hypothesis that boric acid and probably other boron-containing compounds can displace steroid hormones from their plasma carriers. If such phenomena are confirmed, boron administration with a clear mechanism could be employed as a therapeutic agent in several diseases or physiological events that require modulation of steroid hormone levels in plasma.

Profile of three boron-containing compounds on the body weight, metabolism and inflammatory markers of diabetic rats

It has been reported that boron induces changes in carbohydrate and lipid metabolism, body weight and inflammatory processes. This is relevant to the biomedical field due to the requirement for developing therapeutic tools with potential application in metabolic disorders affecting humankind. However, most of the reported data from both humans and animals were obtained after boron was administered as borax or boric acid. In this work, we determined the effects of boric, cyclohexylboronic (CHB) and phenylboronic (PBA) acids (10 mg/kg of body weight/daily for two weeks) on the body weight, metabolism and inflammatory markers in the blood of control, fat-feeding and experimental diabetic rats. In particular, we observed the effects of the administration of these compounds on glycaemia and cholesterol, triglyceride, insulin, IL-6 and C-reactive protein levels, as well as visceral fat and body weight. We found different profiles for each boron-containing compound: boric acid induced decreasing body weight, insulin and IL-6 levels; CHB administration induced an increase in body weight and cholesterol but decreased IL-6 levels; and PBA administration induced a decrease in visceral fat and glucose and insulin levels. These results can improve the understanding of boron as a metabolic regulator and help develop new potential strategies to use compounds with this trace element for therapeutic purposes.