Current Neuropharmacology - Volume 5, Issue 4, 2007

G-protein-coupled receptors (GPCRs), which are encoded by >300 genes in the human genome, are by far the largest class of targets for modern drugs. These macromolecules display inherent adaptability of function, which is partly due to the production of different forms of the receptor protein. These are commonly called ‘isoforms’ or ‘splice variants’ denoting the molecular process of their production/ assembly. Not all GPCRs are expressed as splice variants, but certain subclasses of 5-HT receptors are for example, the 5-HT4 and 5-HT7 receptors. There are at least 11 human 5-HT4 and three h5-HT7 receptor splice variants. This review describes their discoveries, nomenclature and structures. The discovery that particular splice variants are tissue specific (or prominent) has highlighted their potential as future drug targets. In particular, this review examines the functional relevance of different 5-HT4 and 5-HT7 receptor splice variants. Examples are given to illustrate that splice variants have differential modulatory influences on signalling processes. Differences in agonist potency and efficacies and also differences in desensitisation rates to 5-HT occur with both 5-HT4 and 5-HT7 receptor splice variants. The known and candidate signalling systems that allow for splice variant specific responses include GPCR interacting proteins (GIPs) and GPCR receptor kinases (GRKs) which are examined. Finally, the relevance of 5-HT receptor splice variants to clinical medicine and to the pharmaceutical industry is discussed.

From the initial characterizations of inflammatory responses in Alzheimer's disease (AD) affected brains, namely the demonstration of activated microglia and reactive astrocytes, complement system activation, increased production of proinflammatory cytokines, and evidence for microglial-produced neurotoxins, there was hope that reducing inflammation might be a feasible treatment for this memory-robbing disease. This hope was supported by a number of epidemiology studies demonstrating that patients who took nonsteroidal anti-inflammatory drugs had significantly lower risk of developing AD. However, clinical trials of anti-inflammatories have not shown effectiveness, and in recent years, the concept of immune therapy has become a treatment option as animal studies and clinical trials with Aβ vaccines have demonstrated enhanced amyloid removal through stimulation of microglial phagocytosis. This review will examine the current status of whether inhibiting inflammation is a valid therapeutic target for treating AD; what lessons have come from the clinical trials; what new pathways and classes of agents are being considered; and how this field of research can progress towards new therapeutics. We will examine a number of agents that have shown effectiveness in reducing inflammation amongst other demonstrated mechanisms of action. The major focus of much AD drug discovery has been in identifying agents that have antiamyloid properties; however, a number of these agents were first identified for their anti-inflammatory properties. As drug development and clinical testing is a costly and lengthy endeavor, sound justification of new therapeutic targets is required. Possible future directions for AD anti-inflammatory or immune clearance therapy will be discussed based on recent experimental data.

The extracellular signal-regulated kinases 1 and 2 (ERK) cascade, member of the mitogen-activated protein kinases superfamily of signalling pathways, is one of the best characterized pathways as many protein interactions and phosphorylation events have been systematically studied. Traditionally, ERK are associated with the regulation of proliferation and differentiation as well as survival of various cell types. Their activity is controlled by phosphorylation on specific aminoacidic residues, which is induced by a variety of external cues, including growth-promoting factors. In the nervous system, ERK phosphorylation is induced by binding of neurotrophins to their specific tyrosine kinase receptors or by neuronal activity leading to glutamate release and binding to its ionotropic and metabotropic receptors. Some studies have provided evidence of its importance in neuroplastic events. In particular, ERK phosphorylation in the spinal cord was shown to be nociceptive-specific and its upregulation, occurring in cases of chronic inflammatory and neuropathic pain, seems to be of the utmost importance to behavioural changes observed in those conditions. In fact, experiments using specific inhibitors of ERK phosphorylation have proved that ERK directly contributes to allodynia and hyperalgesia caused by spinal cord injury or chronic pain. Additionally, spinal ERK phosphorylation regulates the micturition reflex in experimental models of bladder inflammation and chronic spinal cord transection. In this review we will address the main findings that suggest that ERK might be a future therapeutic target to treat pain and other complications arising from chronic pain or neuronal injury.

Cell adhesion molecules (CAMs) play a pivotal role in the development and maintenance of the nervous system under normal conditions. They also are involved in numerous pathological processes such as inflammation, degenerative disorders, and cancer, making them attractive targets for drug development. The majority of CAMs are signal transducing receptors. CAM-induced intracellular signalling is triggered via homophilic (CAM-CAM) and heterophilic (CAM - other counter-receptors) interactions, which both can be targeted pharmacologically. We here describe the progress in the CAM pharmacology focusing on cadherins and CAMs of the immunoglobulin (Ig) superfamily, such as NCAM and L1. Structural basis of CAM-mediated cell adhesion and CAM-induced signalling are outlined. Different pharmacological approaches to study functions of CAMs are presented including the use of specific antibodies, recombinant proteins, and synthetic peptides. We also discuss how unravelling of the 3D structure of CAMs provides novel pharmacological tools for dissection of CAM-induced signalling pathways and offers therapeutic opportunities for a range of neurological disorders.

Different classes of neurons in the CNS utilize endogenous cannabinoids as retrograde messengers to shape afferent activity in a short- and long-lasting fashion. Transient suppression of excitation and inhibition as well as long-term depression or potentiation in many brain regions require endocannabinoids to be released by the postsynaptic neurons and activate presynaptic CB1 receptors. Memory consolidation and/or extinction and habit forming have been suggested as the potential behavioral consequences of endocannabinoidmediated synaptic modulation. However, endocannabinoids have a dual role: beyond a physiological modulation of synaptic functions, they have been demonstrated to participate in the mechanisms of neuronal protection under circumstances involving excessive excitatory drive, glutamate excitotoxicity, hypoxia-ischemia, which are key features of several neurodegenerative disorders. In this framework, the recent discovery that the endocannabinoid 2-arachidonoyl-glycerol is released by midbrain dopaminergic neurons, under both physiological synaptic activity to modulate afferent inputs and pathological conditions such as ischemia, is particularly interesting for the possible implication of these molecules in brain functions and dysfunctions. Since dopamine dysfunctions underlie diverse neuropsychiatric disorders including schizophrenia, psychoses, and drug addiction, the importance of better understanding the correlation between an unbalanced endocannabinoid signal and the dopamine system is even greater. Additionally, we will review the evidence of the involvement of the endocannabinoid system in the pathogenesis of Parkinson's disease, where neuroprotective actions of cannabinoid-acting compounds may prove beneficial. The modulation of the endocannabinoid system by pharmacological agents is a valuable target in protection of dopamine neurons against functional abnormalities as well as against their neurodegeneration.

Synergisms between pharmacological agents and endogenous neurotransmitters are familiar and frequent. The present review describes the experimental evidence for interactions between neuropharmacological compounds and the classes of weak magnetic fields that might be encountered in our daily environments. Whereas drugs mediate their effects through specific spatial (molecular) structures, magnetic fields mediate their effects through specific temporal patterns. Very weak (microT range) physiologically-patterned magnetic fields synergistically interact with drugs to strongly potentiate effects that have classically involved opiate, cholinergic, dopaminergic, serotonergic, and nitric oxide pathways. The combinations of the appropriately patterned magnetic fields and specific drugs can evoke changes that are several times larger than those evoked by the drugs alone. These novel synergisms provide a challenge for a future within an electromagnetic, technological world. They may also reveal fundamental, common physical mechanisms by which magnetic fields and chemical reactions affect the organism from the level of fundamental particles to the entire living system.

(-)-Stepholidine (SPD), a natural product isolated from the Chinese herb Stephania, possesses dopamine (DA) D1 partial agonistic and D2 antagonistic properties in the nigrostriatal and mesocorticolimbic DAergic pathways. These unique dual effects have suggested that SPD can effectively restore previously imbalanced functional linkage between D1 and D2 receptors under schizophrenic conditions, in which, SPD improves both the negative and positive symptoms of schizophrenia. SPD also relieves the motor symptoms of Parkinson's disease (PD) when co-administered with Levodopa. Furthermore, SPD exhibits neuroprotective effects through an antioxidative mechanism and slows down the progression of neuronal degeneration in the substantia nigra (SN) of PD patients and/or animal models. Therefore, SPD is a novel, natural compound with potentially therapeutic roles in the treatment of schizophrenia and/or PD.