Verónica Pérez-De La Cruz

Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects of L-carnitine

Excitotoxicity and disrupted energy metabolism are major events leading to nerve cell death in neurodegenerative disorders. These cooperative pathways share one common aspect: triggering of oxidative stress by free radical formation. In this work, we evaluated the effects of the antioxidant and energy precursor, levocarnitine (l‐CAR), on the oxidative damage and the behavioral, morphological, and neurochemical alterations produced in nerve tissue by the excitotoxin and free radical precursor, quinolinic acid (2,3‐pyrindin dicarboxylic acid; QUIN), and the mitochondrial toxin, 3‐nitropropionic acid (3‐NP). Oxidative damage was assessed by the estimation of reactive oxygen species formation, lipid peroxidation, and mitochondrial dysfunction in synaptosomal fractions. Behavioral, morphological, and neurochemical alterations were evaluated as markers of neurotoxicity in animals systemically administered with l‐CAR, chronically injected with 3‐NP and/or intrastriatally infused with QUIN. At micromolar concentrations, l‐CAR reduced the three markers of oxidative stress stimulated by both toxins alone or in combination. l‐CAR also prevented the rotation behavior evoked by QUIN and the hypokinetic pattern induced by 3‐NP in rats. Morphological alterations produced by both toxins (increased striatal glial fibrillary acidic protein‐immunoreactivity for QUIN and enhanced neuronal damage in different brain regions for 3‐NP) were reduced by l‐CAR. In addition, l‐CAR prevented the synergistic action of 3‐NP and QUIN to increase motor asymmetry and depleted striatal GABA levels. Our results suggest that the protective properties of l‐CAR in the neurotoxic models tested are mostly mediated by its characteristics as an antioxidant agent.

3-Nitropropionic acid as a tool to study the mechanisms involved in Huntington's disease: past, present and future.

Huntington’s disease (HD) is an inheritable autosomal-dominant disorder whose causal mechanisms remain unknown. Experimental models have begun to uncover these pathways, thus helping to understand the mechanisms implicated and allowing for the characterization of potential targets for new therapeutic strategies. 3-Nitropropionic acid is known to produce in animals behavioural, biochemical and morphologic changes similar to those occurring in HD. For this reason, this phenotypic model is gaining attention as a valuable tool to mimick this disorder and further developing new therapies. In this review, we will focus on the past and present research of this molecule, to finally bring a perspective on what will be next in this promising field of study.

Quinolinic Acid, an Endogenous Molecule Combining Excitotoxicity, Oxidative Stress and Other Toxic Mechanisms

Quinolinic acid (QUIN), an endogenous metabolite of the kynurenine pathway, is involved in several neurological disorders, including Huntingtons disease, Alzheimers disease, schizophrenia, HIV associated dementia (HAD) etc. QUIN toxicity involves several mechanisms which trigger various metabolic pathways and transcription factors. The primary mechanism exerted by this excitotoxin in the central nervous system (CNS) has been largely related with the overactivation of N-methyl-D-aspartate receptors and increased cytosolic Ca2+ concentrations, followed by mitochondrial dysfunction, cytochrome c release, ATP exhaustion, free radical formation and oxidative damage. As a result, this toxic pattern is responsible for selective loss of middle size striatal spiny GABAergic neurons and motor alterations in lesioned animals. This toxin has recently gained attention in biomedical research as, in addition to its proven excitotoxic profile, a considerable amount of evidence suggests that oxidative stress and energetic disturbances are major constituents of its toxic pattern in the CNS. Hence, this profile has changed our perception of how QUIN-related disorders combine different toxic mechanisms resulting in brain damage. This review will focus on the description and integration of recent evidence supporting old and suggesting new mechanisms to explain QUIN toxicity.

Quinolinic Acid: An Endogenous Neurotoxin with Multiple Targets

Quinolinic acid (QUIN), a neuroactive metabolite of the kynurenine pathway, is normally presented in nanomolar concentrations in human brain and cerebrospinal fluid (CSF) and is often implicated in the pathogenesis of a variety of human neurological diseases. QUIN is an agonist of N-methyl-D-aspartate (NMDA) receptor, and it has a high in vivo potency as an excitotoxin. In fact, although QUIN has an uptake system, its neuronal degradation enzyme is rapidly saturated, and the rest of extracellular QUIN can continue stimulating the NMDA receptor. However, its toxicity cannot be fully explained by its activation of NMDA receptors it is likely that additional mechanisms may also be involved. In this review we describe some of the most relevant targets of QUIN neurotoxicity which involves presynaptic receptors, energetic dysfunction, oxidative stress, transcription factors, cytoskeletal disruption, behavior alterations, and cell death.

S-Allylcysteine prevents the rat from 3-nitropropionic acid-induced hyperactivity, early markers of oxidative stress and mitochondrial dysfunction

We investigated the effects of S-allylcysteine (SAC) on early behavioral alterations, striatal changes in superoxide dismutase (SOD) activity, lipid peroxidation (LP) and mitochondrial dysfunction induced by the systemic infusion of 3-nitropropionic acid (3-NPA) to rats. SAC (300 mg/kg, i.p.), given to animals 30 min before 3-NPA (30 mg/kg, i.p.), prevented the hyperkinetic pattern evoked by the toxin. In addition, 3-NPA alone produced decreased activities of manganese- (Mn-SOD) and copper/zinc-dependent superoxide dismutase (Cu,Zn-SOD), increased LP (evaluated as the formation of lipid fluorescent products) and produced mitochondrial dysfunction in the striatum (measured as decreased 3-(3,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction). In contrast, pretreatment of 3-NPA-injected rats with SAC resulted in a significant prevention of all these markers. Our findings suggest that the protective actions of SAC are related with its antioxidant properties, which in turn may be accounting for the preservation of SOD activity and primary mitochondrial tasks.

Protective effect of S-allylcysteine on 3-nitropropionic acid-induced lipid peroxidation and mitochondrial dysfunction in rat brain synaptosomes.

3-Nitropropionic acid is a neurotoxin that irreversibly inhibits succinate dehydrogenase, a relevant enzyme constituting the complex II of the respiratory chain during mitochondrial electron transport. 3-Nitropropionic acid is known to produce oxidative/nitrosative stress and evokes an experimental model of Huntingtons disease. In this work we evaluated the effects of the antioxidant compound and major organosulfur garlic derivative, S-allylcysteine, on lipid peroxidation and mitochondrial dysfunction induced by 3-nitropropionic acid in synaptosomal fractions from rat brain. 3-Nitropropionic acid, at concentrations ranging 0.75-2.5 mM, produced enhanced levels of lipid peroxidation, while increasing concentrations of S-allylcysteine (0.1-2 mM) decreased the peroxidative action of 3-nitropropionic acid (1 mM) in synaptosomal fractions in a concentration-dependent manner. S-Allylcysteine (0.75 mM) also prevented the 3-nitropropionic acid (1mM)-induced mitochondrial dysfunction. These findings suggest that the protective actions that S-allylcysteine exert on the in vitro neurotoxicity induced by 3-nitropropionic acid are mediated by its antioxidant properties.

Lipid peroxidation, mitochondrial dysfunction and neurochemical and behavioural deficits in different neurotoxic models: Protective role of S-allylcysteine

Experimental evidence on the protective properties of S-allylcysteine (SAC) was collected from three models exerting striatal toxicity. In the first model, SAC (120mg kg−1×5) prevented lipoperoxidation (LP) and mitochondrial dysfunction (MD) in synaptosomal fractions from 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridinium-treated mice (30mg kg−1), but without complete restoration of dopamine levels. In the second model, SAC (300mg kg−1×3), prevented LP and MD in synaptosomes from rats infused with 6-hydroxydopamine (8µg µl−1) into the substantia nigra pars compacta, but again, without total reversion of depleted dopamine levels. In the third model, SAC (100 mg kg−1×1) prevented MD in synaptosomes from rats injected with 3-nitropropionic acid (10 mg kg−1), but in contrast to the other models, it failed to prevent LP. SAC also prevented the aberrant motor activity patterns evoked by the three toxins. Altogether, the results suggest that the antioxidant properties of SAC are responsible for partial or total preservation of neurochemical, biochemical and behavioural markers, indicating that pro-oxidant reactions underlie the neurotoxicity in these models.

Initial Immunopathogenesis of Multiple Sclerosis: Innate Immune Response

Multiple sclerosis (MS) is an inflammatory, demyelinating, and neurodegenerative disease of the central nervous system. The hallmark to MS is the demyelinated plaque, which consists of a well-demarcated hypocellular area characterized by the loss of myelin, the formation of astrocytic scars, and the mononuclear cell infiltrates concentrated in perivascular spaces composed of T cells, B lymphocytes, plasma cells, and macrophages. Activation of resident cells initiates an inflammatory cascade, leading to tissue destruction, demyelination, and neurological deficit. The immunological phenomena that lead to the activation of autoreactive T cells to myelin sheath components are the result of multiple and complex interactions between environment and genetic background conferring individual susceptibility. Within the CNS, an increase of TLR expression during MS is observed, even in the absence of any apparent microbial involvement. In the present review, we focus on the role of the innate immune system, the first line of defense of the organism, as promoter and mediator of cross reactions that generate molecular mimicry triggering the inflammatory response through an adaptive cytotoxic response in MS.

Kynurenine Pathway and Disease: An Overview

Kynurenine pathway is gaining more and more attention every day in biomedical research since this catabolic route for tryptophan decomposition is not only implicated in different neurological disorders, but also possesses neuroactive metabolites with different biological properties, such as pro-oxidant and antioxidant regulators. Thus, the intensive research on this metabolic pathway is helping us to understand those mechanisms underlying neurodegenerative events during the occurrence of pathological process in the central nervous system (CNS), thereby allowing the design of potential therapies for those disorders involving excitotoxic, oxidative and inflammatory components. Here we intend to provide a brief overview on the relevance of this route for several CNS disorders, and discuss recent information on the different biological properties of the neuroactive metabolites of this pathway and their significance for further research.

Application of Nanoparticles on Diagnosis and Therapy in Gliomas

Glioblastoma multiforme (GBM) is one of the most deadly diseases that affect humans, and it is characterized by high resistance to chemotherapy and radiotherapy. Its median survival is only fourteen months, and this dramatic prognosis has stilled without changes during the last two decades; consequently GBM remains as an unsolved clinical problem. Therefore, alternative diagnostic and therapeutic approaches are needed for gliomas. Nanoparticles represent an innovative tool in research and therapies in GBM due to their capacity of self-assembly, small size, increased stability, biocompatibility, tumor-specific targeting using antibodies or ligands, encapsulation and delivery of antineoplastic drugs, and increasing the contact surface between cells and nanomaterials. The active targeting of nanoparticles through conjugation with cell surface markers could enhance the efficacy of nanoparticles for delivering several agents into the tumoral area while significantly reducing toxicity in living systems. Nanoparticles can exploit some biological pathways to achieve specific delivery to cellular and intracellular targets, including transport across the blood-brain barrier, which many anticancer drugs cannot bypass. This review addresses the advancements of nanoparticles in drug delivery, imaging, diagnosis, and therapy in gliomas. The mechanisms of action, potential effects, and therapeutic results of these systems and their future applications in GBM are discussed.