Sepsis-Associated Encephalopathy and Blood-Brain Barrier Dysfunction.

Sepsis is a life-threatening clinical condition caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis, which is associated with increased morbidity and mortality. SAE clinical presentation may range from mild confusion and delirium to severe cognitive impairment and deep coma. Important mechanisms associated with SAE include excessive microglial activation, impaired endothelial barrier function, and blood-brain barrier (BBB) dysfunction. Endotoxemia and pro-inflammatory cytokines produced systemically during sepsis lead to microglial and brain endothelial cell activation, tight junction downregulation, and increased leukocyte recruitment. The resulting neuroinflammation and BBB dysfunction exacerbate SAE pathology and aggravate sepsis-induced brain dysfunction. In this mini-review, recent literature surrounding some of the mediators of BBB dysfunction during sepsis is summarized. Modulation of microglial activation, endothelial cell dysfunction, and the consequent prevention of BBB permeability represent relevant therapeutic targets that may significantly impact SAE outcomes.

Unraveling the Role of Astrocytes in Subthalamic Nucleus Deep Brain Stimulation in a Parkinson's Disease Rat Model.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective therapeutic strategy for motor symptoms of Parkinson's disease (PD) when L-DOPA therapy induces disabling side effects. Classical inflammatory activation of glial cells is well established in PD, contributing to the progressive neurodegenerative state; however, the role of DBS in regulating the inflammatory response remains largely unknown. To understand the involvement of astrocytes in the mechanisms of action of DBS, we evaluated the effect of STN-DBS in regulating motor symptoms, astrocyte reactivity, and cytokine expression in a 6-OHDA-induced PD rat model. To mimic in vivo DBS, we investigate the effect of high-frequency stimulation (HFS) in cultured astrocytes regulating cytokine induction and NF-κB activation. We found that STN-DBS improved motor impairment, induced astrocytic hyperplasia, and reversed increased IFN-γ and IL-10 levels in the globus pallidus (GP) of lesioned rats. Moreover, HFS activated astrocytes and prevented TNF-α-induced increase of monocyte chemoattractant protein-1 (MCP-1) and NF-κB activation in vitro. Our results indicate that DBS/HFS may act as a regulator of the inflammatory response in PD states, attenuating classical activation of astrocytes and cytokine induction, potentially through its ability to regulate NF-κB activation. These findings may help us understand the role of astrocyte signaling in HFS, highlighting its possible relationship with the effectiveness of DBS in neurodegenerative disorders.

Monoaminergic regulation of nociceptive circuitry in a Parkinson's disease rat model.

Pain is a common nonmotor symptom of Parkinson's disease (PD) that remains neglected and misunderstood. Elucidating the nondopaminergic circuitry may be key to better understanding PD and improving current treatments. We investigated the role of monoamines in nociceptive behavior and descending analgesic circuitry in a rat 6-hydroxydopamine (6-OHDA)-induced PD model and explored the resulting motor dysfunctions and inflammatory responses. Rats pretreated with noradrenaline and serotonin reuptake inhibitors were given unilateral striatal 6-OHDA injections and evaluated for mechanical hyperalgesia and motor impairments. Through immunohistochemistry, the number and activation of neurons, and the staining for astrocytes, microglia and enkephalin were evaluated in specific brain structures and the dorsal horn of the spinal cord. The PD model induced bilateral mechanical hyperalgesia that was prevented by reuptake inhibitors in the paw contralateral to the lesion. Reuptake inhibitors also prevented postural immobility and asymmetric rotational behavior in PD rats without interfering with dopaminergic neuron loss or glial activation in the substantia nigra. However, the inhibitors changed the periaqueductal gray circuitry, protected against neuronal impairment in the locus coeruleus and nucleus raphe magnus, and normalized spinal enkephalin and glial staining in lesioned rats. These data indicate that the preservation of noradrenergic and serotonergic systems regulates motor responses and nociceptive circuitry during PD not by interfering directly with nigral lesions but by modulating the opioid system and glial response in the spinal cord. Taken together, these results suggest that nondopaminergic circuitry is essential to the motor and nonmotor symptoms of PD and must be further investigated.

Intracerebroventricular Streptozotocin as a Model of Alzheimer's Disease: Neurochemical and Behavioral Characterization in Mice.

Streptozotocin has been widely used to mimic some aspects of Alzheimer's disease (AD). However, especially in mice, several characteristics involved in the streptozotocin (STZ)-induced AD pathology are not well known. The main purpose of this study was to evaluate temporally the expression of AD-related proteins, such as amyloid-ß (Aß), choline acetyltransferase (ChAT), synapsin, axonal neurofilaments, and phosphorylated Tau in the hippocampus following intracerebroventricular (icv) administration of STZ in adult mice. We also analyzed the impact of STZ on short- and long-term memory by novel object recognition test. Male mice were injected with STZ or citrate buffer, and AD-related proteins were evaluated by immunoblotting assays in the hippocampus at 7, 14, or 21 days after injection. No differences between the groups were found at 7 days. The majority of AD markers evaluated were found altered at 14 days, i.e., the STZ group showed increased amyloid-ß protein and neurofilament expression, increased phosphorylation of Tau protein, and decreased synapsin expression levels compared to controls. Except for synapsin, all of these neurochemical changes were transient and did not last up to 21 days of STZ injection. Moreover, both short-term and long-term memory deficits were demonstrated after STZ treatment at 14 and 21 days after STZ treatment.

LTP and LTD in the visual cortex require the activation of NOX2.

Reactive oxygen species (ROS) are signaling factors involved in many intracellular transduction pathways. In the nervous system, ROS are thought to modulate various mechanisms of synaptic plasticity. One important source of ROS production in the brain is the NADPH oxidase complex. Stimulation of NMDA receptors activates NADPH oxidase, which provides selective oxidative responses accompanying the induction of synaptic changes. The activity of NADPH oxidase is known to be crucial for the induction of LTP in the hippocampus. However, the involvement of this complex in cortical synaptic plasticity is still unclear. Here we provide evidence that genetic ablation of NOX2 (the prototypical member of NADPH oxidase family of proteins) suppresses LTP and LTD in the primary visual cortex of the mouse. We also found that the involvement of NOX2 on LTP is partially age-dependent, as the activity of this complex is not critical for mechanisms of synaptic potentiation occurring in immature animals. Furthermore, we show that inhibition of NOX2 reduces the NMDA receptor function, suggesting a possible mechanism that could be the basis of the effects on synaptic plasticity.

Glycine as a neurotransmitter in the forebrain: a short review.

Since the late 1970s glycine has been considered an important inhibitory neurotransmitter in brain stem and medulla. The description of its involvement in the mechanism of action of the potent neurotoxin strychnine pushed further the concept of inhibitory transmitter. The significant concentrations of glycine in forebrain motivated investigators to evaluate different aspects of glycinergic transmission under the ontogenetic, physiologic and pathologic standpoints. This review encompasses a few of these aspects as the role of the different glycine receptors (GlyRs) in intracellular chloride balance, glycine transporters, GABA/Glycine co-release, glycine/NMDA receptor interaction, glycine receptors in acute alcohol effects and advocates a more relevant role for glycine as a stimulatory transmitter in forebrain areas. Finally, the possible co-release of glycine and GABA is considered as an important process to understand the role of glycine in forebrain neural transmission.

Glycine stimulates the release of labeled acetylcholine but not dopamine nor glutamate from superfused rat striatal tissue.

Glycine is known as an inhibitory neurotransmitter in the spinal cord and forebrain but its precise role in the forebrain is largely overlooked. This investigation evaluated whether glycine alters acetylcholine, glutamate or dopamine release from striatal tissue using an in vitro approach. We observed that while glycine induced a robust (3)H-acetylcholine release ((3)H-ACh) from superfused striatal tissue, it failed at releasing (3)H-glutamate or (3)H-dopamine. Glycine stimulated (3)H-ACh release in a dose- and calcium-dependent manner (EC(50)=69 microM). Tetrodotoxin (1 microM) inhibited about 75% of the release demonstrating a predominant dendritic and cell body location of glycine receptors. The prototypical glycine receptor antagonist strychnine at 10 microM completely abolished (3)H-ACh release. To further characterize the role of striatal glycine receptors in (3)H-ACh release we examined glycine effects after in vivo treatment with Haloperidol-decanoate (HD). Treatment for 30 days or more with HD decreased maximal glycine-stimulated release of (3)H-ACh suggesting a non-competitive inhibition. After 30 days of washout release parameters did not return to vehicle-treated levels. The glutamate agonist NMDA also stimulated acetylcholine release but showed slightly different behavior in HD-treated striatal tissue. These effects could be attributed to changes in chloride transporters expressed in the giant striatal cholinergic cell as well as glycine receptor subunit composition and finally, GABA/glycine co-release in this tissue.

Glicina como neurotransmissor no corpo estriado de ratos / Glycine as a neurotransmitter in rat striatal tissue

A glicina é um aminoácido encontrado em todos os fluidos e tecidos corporais em quantidades substanciais. Além de possuir propriedades antiinflamatórias, citoprotetoras e imunomodulatórias este aminoácido também atua como um neurotransmissor inibitório, regulando a excitabilidade de neurônios do tronco cerebral e da medula espinhal. Muito embora, sua ação inibitória em estruturas prosencefálicas seja controversa. Neste estudo, a fim de avaliar o papel da glicina como neurotransmissor no tecido estriatal de ratos, foram realizados ensaios de liberação de neurotransmissores marcados radioativamente. Demonstrou-se que a glicina induz a liberação de acetilcolina do através de um mecanismo sensível a estricnina. Esta liberação mostrou-se concentração-dependente e o efeito máximo foi atingido a partir de 300 µM. A ausência de Ca2+ diminuiu de maneira consistente a liberação e a presença de TTX bloqueou parcialmente o estímulo glicinérgico (75 por cento), indicando que os receptores responsáveis pelo fenômeno observado estão localizados nos dendritos e no corpo celular presumivelmente de interneurônios colinérgicos. Em vista dos efeitos do tratamento prolongado com haloperidol, um antagonista dopaminérgico de largo emprego clínico, sobre os interneurônios colinérgicos estriatais, empregou-se esta droga para avaliar possíveis alterações da resposta à glicina e ao NMDA neste modelo experimental. Para a realização destes experimentos, ratos foram injetados por via i.m. (21 mg/kg i.m.), durante 15, 30 ou 60 dias com haloperidol decanoato ou com o veículo de diluição da droga, óleo de gergelim. Com 15 dias de tratamento já se pode notar uma redução significativa na liberação máxima de acetilcolina estimulada por glicina (300 µM) e por NMDA (100 µM). Após 30 e 60 dias de tratamento, esta redução não se mostrou maior. Em estudos adicionais, foram realizados experimentos 15 e 30 dias após o término da metabolização da droga, para avaliar se tais períodos seriam suficientes para que o tecido recuperasse os níveis normais de liberação de acetilcolina estimulada por glicina. A liberação máxima foi alcançada após estes períodos, da mesma maneira que a liberação de acetilcolina estimulada por NMDA. Apomorfina (1 µM), reduziu significativamente a liberação de acetilcolina estimulada por glicina porém, este efeito não foi maior no tecido de animais tratados por 30 dias...(AU)