Facultad de Ciencias de la Salud

Different mechanisms have been suggested for cocaine neurotoxicity, including oxidative stress alterations. Nuclear factor kappa B (NF-κB), considered a sensor of oxidative stress and inflammation, is involved in drug toxicity and addiction. NF-κB is a key mediator for immune responses that induces microglial/macrophage activation under inflammatory processes and neuronal injury/degeneration. Although cerebellum is commonly associated to motor control, muscular tone, and balance. Its relation with addiction is getting relevance, being associated to compulsive and perseverative behaviors. Some reports indicate that cerebellar microglial activation induced by cannabis or ethanol, promote cerebellar alterations and these alterations could be associated to addictive-related behaviors. After considering the effects of some drugs on cerebellum, the aim of the present work analyzes pro-inflammatory changes after cocaine exposure. Rats received daily 15 mg/kg cocaine i.p., for 18 days. Reduced and oxidized forms of glutathione (GSH) and oxidized glutathione (GSSG), glutathione peroxidase (GPx) activity and glutamate were determined in cerebellar homogenates. NF-κB activity, CD68, and GFAP expression were determined. Cerebellar GPx activity and GSH/GSSG ratio are significantly decreased after cocaine exposure. A significant increase of glutamate concentration is also observed. Interestingly, increased NF-κB activity is also accompanied by an increased expression of the lysosomal mononuclear phagocytic marker ED1 without GFAP alterations. Current trends in addiction biology are focusing on the role of cerebellum on addictive behaviors. Cocaine-induced cerebellar changes described herein fit with previosus data showing cerebellar alterations on addict subjects and support the proposed role of cerebelum in addiction.

(1) Background: Retinitis pigmentosa (RP) is characterized by progressive photoreceptor death. A Prph2Rd2 or an rds mouse is an RP model that closely reflects human RP. The objective of this study was to investigate the relationship of rod and cone death with oxidative stress and inflammation in rds mice. (2) Methods: The retinas of control and rds mice on postnatal days (PN) 11, 17, 21, 28, 35, and 42 were used. Oxidative damage to macromolecules, glutathione (GSH and GSSG), GSH synthesis enzymes, glial fibrillar acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba1), and cluster of differentiation 68 (CD68) was studied. (3) Results: The time sequence of oxidative stress and inflammation changes in rds mice occurs as follows: (i) At PN11, there is a small increase in photoreceptor death and in the microglial cells; (ii) at PN17, damage to the macromolecules is observed; (iii) at PN21, the maximum photoreceptor death rate is detected and there is an increase in GSH-GSSG and GFAP; (iv) at PN21, the microglial cells are activated; and(v) at PN28, there is a decrease in GSH synthesis enzymes. (4) Conclusions: These findings contribute to the understanding of RP physiopathology and help us to understand whether oxidative stress and inflammation are therapeutic targets. These findings contribute to our understanding that, in RP, oxidative stress and inflammation evolution and their relationship are time-dependent. In this sense, it is important to highlight that both processes are potential therapeutic targets in this disease.

Cocaine can induce severe neurobehavioral changes, among others, the ones involved in learning and memory processes. It is known that during drug consumption, cocaine-associated memory and learning processes take place. However, much less is known about the effects of this drug upon the mechanisms involved in forgetting.The present report focuses on the mechanisms by which cocaine affects memory consolidation of experiences acquired prior to drug administration. We also study the involvement of hippocampus in these processes, with special interest on the role of Nuclear factor kappa B (NF-κB), N-methyl-D-aspartate glutamate receptor 2B (GluN2B), and their relationship with other proteins, such as cyclic AMP response element binding protein (CREB). For this purpose, we developed a rat experimental model of chronic cocaine administration in which spatial memory and the expression or activity of several proteins in the hippocampus were assessed after 36 days of drug administration. We report an impairment in memory acquisition of experiences gathered prior to cocaine administration, associated to an increase in GluN2B expression in the hippocampus. We also demonstrate a decrease in NF-κB activity, as well as in the expression of the active form of CREB, confirming the role of these transcription factors in the cocaine-induced memory impairment.

Goal-directed navigation can be based on world-centered (allocentric) or body-centered (egocentric) representations of the environment, mediated by a wide network of interconnected brain regions, including hippocampus, striatum and prefrontal cortex. The relative contribution of these regions to navigation from novel or familiar routes, that demand a different degree of flexibility in the use of the stored spatial representations, has not been completely explored. To address this issue, we trained mice to find a reward relying on allocentric or egocentric information, in a modified version of the cross-maze task. Then we used Zif268 expression to map brain activation when well-trained mice were required to find the goal from a novel or familiar location. Successful navigation was correlated with the activation of CA1, posterior-dorsomedial striatum, nucleus accumbens core and infralimbic cortex when allocentric-trained mice needed to use a novel route. Allocentric navigation from a familiar route activated dorsomedial striatum, nucleus accumbens, prelimbic and infralimbic cortex. None of the structures analyzed was significantly activated in egocentric-trained mice, irrespective of the starting position. These data suggest that a flexible use of stored allocentric information, that allows goal finding even from a location never explored during training, induces a shift from fronto-striatal to hippocampal circuits.

Oxidative stress has been documented to be a key factor in the cause and progression of different retinal diseases. Oxidative cellular unbalance triggers a sequence of reactions which prompt cell degeneration and retinal dysfunction, both hallmarks of several retinal pathologies. There is no effective treatment, yet, for many retinal diseases. Antioxidant treatment have been pointed out to be an encouraging palliative treatment; the beneficial effects documented involve slowing the progression of the disease, a reduction of cell degeneration, and improvement of retinal functions. There is a vast information corpus on antioxidant candidates. In this review, we expose three of the main antioxidant treatments, selected for their promising results that has been reported to date. Recently, the sulforaphane, an isothiocyanate molecule, has been unveiled as a neuroprotective candidate, by its antioxidant properties. Progesterone, a neurosteroid has been proposed to be a solid and effective neuroprotective agent. Finally, the lipoic acid, an organosulfur compound, is a well-recognized antioxidant. All of them, have been tested and studied on different retinal disease models. In this review, we summarized the published results of these works, to offer a general view of the current antioxidant treatment advances, including the main effects and mechanisms described.

Retinitis pigmentosa (RP) is a group of inherited retinopathies characterized by photoreceptors death. Our group has shown the positive progesterone (P4) actions on cell death progression in an experimental model of RP. In an effort to enhance the beneficial effects of P4, the aim of this study was to combine P4 treatment with an antioxidant [lipoic acid (LA)] in the rd1 mice. rd1 and control mice were treated with 100 mg/kg body weight of P4, LA, or a combination of both on postnatal day 7 (PN7), 9, and 11, and were sacrificed at PN11. The administration of LA and/or P4 diminishes cell death in rd1 retinas. The effect obtained after the combined administration of LA and P4 is higher than the one obtained with LA or P4 alone. The three treatments decreased GFAP staining, however, in the far peripheral retina, and the two treatments that offered better results were LA and LA plus P4. LA or LA plus P4 increased retinal glutathione (GSH) concentration in the rd1 mice. Although LA and P4 are able to protect photoreceptors from death in rd1 mice retinas, a better effectiveness is achieved when administering LA and P4 at the same time.