Critical reviews in neurobiology最新文献

Neuro-inflammation plays a pivotal role in numerous neurodegenerative disorders, such as Parkinson's disease (PD). Traditional anti-inflammatory drugs have limited therapeutic use because of their narrow spectrum and severe side effects after long-term use. Morphinans are a class of compounds containing the basic morphine structure. The following review will describe novel neuroprotective effects of several morphinans in multiple inflammatory disease models. The potential therapeutic utility and underlying mechanisms of morphinan neuroprotection are discussed.

The GABA-reelin cortical connection (i.e., the expression and secretion of reelin by GABAergic cortical neurons) has been shown to function not only in the adult cortex but also during tangential migration of GABAergic neuroblasts. Therefore, it is of interest to focus on the possibility that a synergic action of these compounds (understood as a topobiological effect, implying place- and time-dependent interactions) may have important implications in regulating developmental processes such as neuronal migration, dendritic sprouting, synaptogenesis, and axon pruning, as well as being involved in regulation of synaptic plasticity trough life. The present review summarizes the actual knowledge in this field and discusses the possible importance that a dysregulation of GABAergic and reelin systems may have as vulnerability factors for the etiology and pathophysiology of schizophrenia.

A considerable volume of evidence implicates the purine adenosine in the regulation of cerebral blood flow during states such as hypotension, neural activation, hypoxia/ischemia, and hypercapnia/acidosis. The aim of this review is to describe developments in our understanding of the roles that adenosine and the adenine nucleotides play in cerebral blood flow control, with some comparisons to coronary blood flow. The first part of the review focuses on the categorization of receptors for adenosine (A1, A2A, A2B, and A3) and the adenine nucleotides, ATP and ADP (P2X and P2Y). Frequently used agonists and antagonists for these different receptors are mentioned. A description follows of the distribution of these different receptors in cerebral arterioles. The second part of the review initially deals with the literature on the release of adenosine and adenine nucleotides into the extracellular space of the brain, describing the various techniques used to make these measurements and assessing the pitfalls associated with their use. This is followed by a discussion of the factors affecting purine release, which include cell swelling and acidosis. The third section evaluates the role of smooth muscle potassium channels in controlling arteriolar diameter. There is evidence for an important role of KATP and KCa channels, but less is known about the contributions of voltage-dependent (KV) and inwardly rectifying (KIR) channels. This section ends with a discussion on the reported inhibitory effect of nitric oxide synthase inhibitors on the KATP channel and the consequences of such an action for the interpretation of much of the published work on nitric oxide as a regulator of cerebral blood flow. The fourth section evaluates the data supporting a role of adenosine and ATP in the regulation of cerebral blood flow during autoregulation, hypotension, neural activity, hypoxia/ ischemia, and hypercapnia. Studies using antagonists and potentiators of adenosine's actions have led to the conclusion that adenosine is involved in vascular flow control, matching metabolic activity to blood flow in all of these conditions, possibly with the exceptions of autoregulation at mean arterial blood pressures above approximately 60 mmHg. Evidence is presented for a major role of A2A, and a more limited role of A2B receptors, in balancing blood flow with metabolism. The primary effect of receptor occupancy is activation of KATP and KCa channels with smooth muscle relaxation and elevated blood flow rates. There are presently fewer data on ATP's participation in flow control, but recent evidence regarding glial cell control of cerebral arteriolar diameter suggests that this may be an important mechanism. The semi-final section, which briefly describes the evidence for a comparable role of adenosine in regulating coronary blood flow, is followed by a concluding statement reaffirming the importance of adenosine as a cerebral blood flow regulator.

Promising therapeutic uses and a great variety of pharmacological effects are the leading forces that focus actual cannabinoid research. Cannabinoid and opioid systems share neuroanatomical, neurochemical, and paharmacological features. This fact supports the notion that actions induced by each one of these types of drugs involved an interaction between the endogenous opioid and endocannabinoid neuronal systems. Over the last decade our group and others have investigated cannabinoid/opioid crosstalk in the central nervous system by studying the mechanisms underlying pharmacological and biochemical interactions between the two systems in experimental paradigms of antinociception, drug reinforcement, and anxiety. The goal of this review is to revise the latest work done on this subject, with special emphasis on the research done with genetically modified animals. Whereas clinical progress is going ahead slowly, basic research in this area is progressing rapidly. Clinical applications derived from the cannabinoid/opioid crosstalk and based tightly on medical evidence are yet to come, but it is hoped that knowledge of this central messenger interaction will help to develop new alternatives for the treatment of some pathological states.

The idea that it should be possible to develop a neuroprotective drug that protects the brain from some of the consequences of an acute ischaemic stroke has been in existence for some time and has developed from our increasing knowledge of the biochemical consequences of an acute ischaemic episode. A variety of drugs have been developed to interfere with these biochemical changes. However, while many of these compounds have been shown to be efficacious in animal models of stroke, none has succeeded in clinical trials and reached the market in the Western world. Partly as a result of these failures, guidelines have been published and further extended that detail criteria that should be met before a novel compound is progressed to clinical investigation. These guidelines are reviewed herein, and the author suggests the probability that none of the compounds that have previously failed clinically would have fulfilled the current selection criteria for advancement to clinical trial. It is proposed that NXY-059 (Cerovive) is the first neuroprotective agent to reach the clinical trial phase that meets all the suggested guidelines for neuroprotective drug development, and the preclinical profile of this compound is reviewed.

There is evidence of an association between depression and anxiety and cardio- cerebro-vascular conditions, but the mechanisms of this association are unknown. Here we review a possible role for the 5-lipoxygenase (5-LOX) pathway. 5-LOX is an enzyme that, in association with 5-LOX-activating protein (FLAP), leads to the synthesis of leukotrienes from omega-6 arachidonic acid. Production of active leukotrienes can be reduced by dietary omega-3 fatty acids, which also are beneficial in cardiac and psychiatric (e.g., depression) pathologies. Human 5-LOX and FLAP gene polymorphisms are a risk factor in atherosclerosis and cardio-cerebro-vascular pathologies; an overactive 5-LOX pathway is found in these diseases. Studies with 5-LOX-deficient transgenic mice suggest that 5-LOX activity may contribute to anxiety- and depression-like behaviors. Future research should characterize the role of the 5-LOX pathway in comorbid cardio-cerebro-vascular and psychiatric disorders and in the therapeutic actions of dietary omega-3 fatty acids.

Genetic, environmental, or hormonal factors and their interactions have been implicated in the expression of gender-related aggressive behavior in humans. Several independent lines of evidence support the role of hormonal and environmental factors in the aggressive behavior of experimental animals. Social isolation (SI) for 2-4 weeks in male but not in female mice results in the expression of aggression to a same-sex intruder. Long-term treatment (3 weeks) with anabolic steroids during SI in female mice induces aggressive behavior toward a male intruder of a severity similar to that observed in socially isolated (SI) male mice. The induced aggression in male and female mice is associated with a decrease of brain allopreg-nanolone (Allo). In SI male mice, aggression can be prevented by treatment with L-methionine (MET), which has also been shown to decrease reelin and GAD67 mRNA expression and maintain normal brain Allo content. The histone deacetylase inhibitor valproic acid can reverse this process, suggesting that histone tail acetylation may reverse the action of MET. We conclude that during social isolation, aggression can be controlled either by preventing Allo downregulation (e.g., by treatment with MET) or by direct administration of Allo or of agents (e.g., fluoxetine) that upregulate brain Allo content in SI mice.

Dopamine reuptake by norepinephrine terminals can occur in brain areas such as the prefrontal cortex, the nucleus accumbens shell, and the bed nucleus of stria terminalis that are innervated, although unevenly, by both dopamine and norepinephrine neurons. Therefore the antidepressants that bind selectively the norepinephrine transporter might produce their therapeutic effect by raising the extracellular concentration of dopamine besides that of norepinephrine. Moreover, cocaine can be reinforcing even in knock-out mice for the dopamine transporter because it might raise synaptic dopamine in the nucleus accumbens shell by preventing its uptake by the norepinephrine transporter, an effect that could take place even in wild animals. Recently, it has also been suggested that dopamine can be co-released with norepinephrine by norepinephrine neurons, although it is not clear whether this feature might be related to a previous nonspecific uptake of dopamine by the norepinephrine transporter. In this review we discuss the potential role of the nonspecific uptake of dopamine by norepinephrine transporter in the mechanism of action of drugs of abuse, antipsychotics, and antidepressants.

The release of [3H]dopamine was measured in rat corticostriatal slice preparations that contained the striatum and the adjacent prefrontal cortex to maintained glutamatergic corticostriatal afferentation. These slices were prepared from either nontreated or 6-hydroxydopamine-pretreated rats. The slices were loaded with [3H]dopamine, submerged in a two-compartment bath so that the cortical region was contained in one compartment, the corpus callosum was passed through a silicone greased slot, and the striatal region was contained in the other compartment. The cortical and the striatal parts were superfused with Krebs-bicarbonate buffer independently. The release of [3H]dopamine was determined from the striatal part at rest and in response to electrical stimulation of the cortical area. Electrical stimulation of the cortical part increased the release of [3H]dopamine from the striatal part of the slices, and this release was found to be higher after lesion of the nigrostriatal dopaminergic pathway with 6-hydroxydopamine. Cortically evoked [3H]dopamine release was even higher in the presence of the dopamine precursor L-DOPA after 6-hydroxdopamine lesion. Perfusion of GYKI-53405, a noncompetitive AMPA receptor antagonist, in combination with L-DOPA further increased both basal and stimulation-evoked [3H]dopamine release, whereas GYKI-53405 by itself did not influence basal [3H]dopamine outflow from striatum. These findings indicate that, in parkinsonian striatum, the stimulatory effect of L-DOPA on dopamine release is potentiated by AMPA receptor blockade, and the antiparkinsonian effect of GYKI-53405 may be due to its L-DOPA sparing effect.

There is currently substantial evidence that Cannabis sativa derivates act on brain reward in a way very similar to other drugs of abuse and exert numerous pharmacological effects through their interaction with various neurotransmitters and neuromodulators. Among them, the endogenous opioids seem to play an important role in modulating the addictive properties of cannabinoids. Given the plethora of research activity on such a topic, this brief review is necessarily focused on cannabinoid/opioid interaction in reward-related events and restricted to the recent literature. Recent findings from our and other laboratories concerning cannabinoid reinforcing effects as revealed by behavioral animal models of addiction are here summarized. Evidence is then provided demonstrating a functional cross-talk between the cannabinoid and opioid systems in the mutual modulation of the addictive behavior; accordingly, very recent data from transgenic mice lacking either the cannabinoid CB1 or opioid receptors are also presented. Finally, the role of the endogenous cannabinoid system in relapse to opioids is investigated by means of extinction/reinstatement animal models following a period, even prolonged, of drug abstinence. Altogether, the reviewed studies provided a better understanding of the neurobiological mechanisms involved in cannabinoid actions and revealed a bidirectional interaction between the endogenous cannabinoid and opioid systems in reward that extends to central mechanisms underlying relapsing phenomena. Challenges for the future involve elucidation of the neuroanatomical substrates of cannabinoids action, even in light of the therapeutic potential of these compounds.