Central Nervous System Agents in Medicinal Chemistry - Volume 7, Issue 1, 2007

Metabotropic glutamate receptors (mGluRs) are a family of G-protein-coupled receptors which play an important role in the modulation of nociception transmission and plasticity [1,2]. In this review we will consider the control of supraspinal nociception by mGluR ligands in several animal models of pain through behavioural and biochemical approaches. More specifically, we will focus our attention on the mGluRs of the midbrain periaqueductal gray (PAG), which has been recognized as an antinociceptive area since 1969. The multiplicity of responses associated with mGluR stimulation is complicated by the localization of these receptors on a variety of pre- and postsynaptic elements of either glutamate, GABA and non-GABA containing neurons that characterize the PAG circuitry. In particular, excitatory-postsynaptic group I mGlu1/5 subtype receptors produce a preferential activation of descending excitatory antinociceptive pathways at the PAG level, while group III mGlu8 receptors modulate the release of glutamate and GABA conversely. Indeed, selective stimulation of mGlu8 receptors generates an increase in glutamate and a decrease in γ-aminobutyric acid (GABA) extracellular levels. These data, together with the evidence that these receptors are present presynaptically on both symmetrical and asymmetrical synapses, justify that their stimulation relieves hyperalgesia in inflammatory pain. Unlike mGlu8, the mGlu7 receptors in the PAG inhibit antinociception via negative modulation of glutamate release, as they seem expressed mainly on asymmetrical synapses. In this review we aim to illustrate the role of mGluRs in controlling nociceptive processes, as well as their interaction with other neurotransmitters within the PAG, in the hope that further findings in this field will pave the way for the development of useful new agents in pain therapy.

Status epilepticus (SE) is clinically defined as prolonged electrical and clinical seizure activity in which the patient does not regain consciousness to a normal alert state between repeated tonic-clonic attacks. The disorder is a neurological emergency associated with a mortality rate of 10-12% and an even greater morbidity. SE can lead to permanent pathological damage and altered physiological function in certain brain regions and induces major changes in membrane phospholipids, massive increases in arachidonic acid concentrations, diacylglycerol-mediated activation, of protein kinase C, calcium-mediated changes in calmodulin kinase II and possibly generation of free radicals that could play an essential role in the mechanism of oxidative stress involved in neural damage. SE can be characterized by a permanent change in neurotransmitter systems and oxidative stress that it is more facilitated in the brain rather than in other tissues because it contains large quantities of oxidizable lipids and metals. The role of monoamines, amino acid and oxidative stress in pilocarpine- induced SE will be investigated in hippocampus, striatum and frontal cortex of adult rats. The SE studied will be induced by pilocarpine (400mg/kg, s.c.) and the results observed were investigated during acute phase. The data obtained suggests that pilocarpine induced amino acid and oxidative stress changes in brain regions that are similar to the one verified in human temporal lobe epilepsy.

Neuromodulators are chemical substances that modify neural responses without directly triggering synaptic excitation. They broadly impact multiple brain functions, such as arousal, sleep, attention, perception, learning, and memory. The noradrenergic neuromodulatory system widely innervates the mammalian brain, including the hippocampus. Hippocampal synaptic plasticity is believed to importantly contribute to the formation and consolidation of some types of memory. Stimulation of noradrenergic receptors in the hippocampus alters neuronal excitability and synaptic plasticity, suggesting a key role for noradrenaline (NA) in learning and memory. Consistent with this notion, NA enhances memory for a variety of hippocampus-dependent tasks. The effects of NA receptor activation on cellular plasticity may account for NA-dependent modulation of memory in the hippocampus. Furthermore, dysfunction of the noradrenergic neuromodulatory system contributes to numerous cognitive and psychiatric disorders. Determining how NA influences information processing at cellular and behavioural levels is essential for understanding the physiology of memory. Such understanding may also reveal new strategies to improve treatments for human memory disorders.

Anorexia nervosa is a debilitating psychiatric disorder characterized by severe dietary restriction and lifethreatening weight loss. The onset of the disorder typically occurs during adolescence with 90-95% of all cases occurring in females. Often characterized by a chronic and relapsing course, anorexia nervosa has one of the highest mortality rates of any psychiatric disorder. Although the etiology is unknown, a complex interplay of genetic, neurobiological, and environmental variables appear to factor into the development of the disorder. Accumulating evidence supports altered serotonin 5-HT1A, 5-HT2A, and 5-HTT receptor binding in anorexia nervosa, with more recent studies examining dopamine D2/D3 receptor binding. Despite this increasing knowledge of neurotransmitter alterations, there are few effective treatment strategies, with pharmacological treatments having minimal efficacy during the acute phase of illness. Thus, the goal of this paper is to provide an overview of neurochemical alterations during the ill state and following long-term recovery. This will be followed by a review of pharmacological treatment studies of anorexia nervosa that will focus on the limited efficacy of SSRIs and more promising findings from atypical antipsychotics. Given the combination of receptors targeted by newer generation atypical antipsychotics, these drugs may provide a more efficient means for modulating the neurobiological disturbances seen in anorexia nervosa.

The intermediates of the kynurenine pathway, called kynurenines, are derived directly or indirectly from the tryptophan metabolism. This metabolic pathway is responsible for nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, which participate in basic cellular processes. It was discovered some thirty years ago that kynurenines have neuroactive properties. Kynurenine, the central compound of this pathway, can be converted to two other important agents: the neuroprotective kynurenic acid and the neurotoxic quinolinic acid. Kynurenic acid is an endogenous broad-spectrum antagonist of excitatory amino acid receptors, including the N-methyl- D-aspartate receptors. It can inhibit the overexcitation of these receptors and reduce the cell damage induced by excitotoxins. Moreover, kynurenic acid non-competitively blocks the α7-nicotinic acetylcholine receptors, thereby permitting modulation of the cholinergic and glutamatergic neurotransmission. Quinolinic acid is a selective N-methyl-D-aspartate receptor agonist which can cause lipid peroxidation, the generation of free radicals and apoptosis via the overexcitation of these receptors. Changes in the relative or absolute concentrations of the kynurenines have been found in several neurodegenerative disorders, such as Huntington's disease and Parkinson's disease, stroke and epilepsy, in which the hyperactivation of amino acid receptors could be involved. Increase of the brain level of kynurenic acid seems to be a good therapeutic strategy; however, kynurenic acid can cross the blood-brain barrier only poorly. The latest findings provide promising opportunities involving the development of the analogues 4-chloro-kynurenine and glucoseamine-kynurenic acid, which can enter the brain and exert neuroprotective effects. Another recent possibility is the use of different enzyme inhibitors which can reduce the production of the neurotoxic quinolinic acid.

Adenosine is an endogenous modulator of several physiological functions in the central nervous system (CNS). The effect is mediated by a receptor family that consists of at least four subtypes: A1, A2A, A2B and A3 receptors. The adenosine receptors play a role in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, epilepsy and schizophrenia. Knowledge on adenosine receptor densities and status are important for understanding the mechanisms underlying the pathogenesis of diseases and for developing new therapeutics. Positron emission tomography (PET) offers a non-invasive tool to investigate these features in vivo, provided that suitable radiopharmaceuticals are available. As a consequence of the development of xanthine-type adenosine receptor antagonists with high affinity and high selectivity, several PET ligands labeled with carbon-11 (half-life of 20.4 min) and fluorine-18 (half-life of 109.8 min) have been proposed for mapping the adenosine A1 and A2A receptors (A1R and A2AR, respectively) and the adenosine uptake site in the CNS since 1995. Later non-xanthine-type antagonists for A2AR were radiolabeled. So far two tracers for A1R, [18F]CPFPX and [11C]MPDX, and a tracer for A2AR, [11C]TMSX (also called [11C]KF18446), have been applied to humans. For the other subtypes and the adenosine uptake site no suitable radioligands have been developed yet. This paper gives an overview of the current status on PET tracers for mapping adenosine receptors and the development of new compounds that may lead to new PET tracers.