CNS & Neurological Disorders - Drug Targets (Formerly Current Drug Targets - CNS & Neurological Disorders) - Volume 10, Issue 5, 2011

Alcoholism and alcohol use disorders (AUDs) impact millions of people and represent a significant global public health problem. According to the World Health Organization, alcoholism related deaths are estimated to account 3.2% of all deaths worldwide. Fetal alcohol syndrome, an important form of mental disability, caused by alcohol abuse and addiction by pregnant women, is on the rise. Previous research suggests that alcoholism is a progressive relapsing disorder of the brain and needs effective treatment to remain abstinent. Due to modest efficacy with currently approved medications, there is a need for new therapeutic strategies for the management of alcoholism. Evidence indicates that neuronal nicotinic acetylcholine receptors (nAChRs) are critical targets for the development of improved pharmacotherapies for alcoholism. However, it is not clear which subtypes of the neuronal nAChR are involved in alcoholism. Recent human genetic association studies have implicated the gene cluster CHRNA3-CHRNA5-CHRNB4 encoding the α3, α5, and β4 subunits of the nAChR in susceptibility to develop nicotine and alcohol dependence, indicating a potential role of these nAChR subunits. To examine the role of the α3 and β4 subunits of the nAChR in alcoholism, Chatterjee and colleagues have developed and characterized high-affinity partial agonists at α3β4 nAChRs, CP-601932, and PF-4575180 in preclinical models of alcoholism. The results suggest that both CP-601932 and PF- 4575180 selectively reduce alcohol but not sucrose self-administration, following long-term exposure. The authors also demonstrated that the functional potencies of CP-601932 and PF-4575180 at α3β4 nAChRs correlate with these compounds' unbound brain concentrations. These data indicate that the effects on alcohol self-administration are mediated by α3β4 nAChRs. Overall, the study suggests that α3β4 nAChRs could be critical therapeutic targets for the treatment of alcoholism and AUDs. In addition, the clinically safe novel partial nAChR agonist CP-601932 has the potential to reduce smoking in alcoholics with co-morbid nicotine dependence. This is due to similar affinity of the novel compound for α4β2 nAChRs that are involved in nicotine addiction. Future clinical studies in subjects with alcoholism and AUDs could further advance its development and use in humans.

Patients with persistent pain present a problem for all clinicians [1, 2]. The International Association for the Study of Pain defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described by the patient in terms of such damage. Although it is generally conceived that pain is always associated with a pathological lesion, the problem with most patients is that the pathology is not easily found. In diseases such as rheumatoid arthritis treating the underlying disease with disease modifying agents (e.g. methotrexate or anti-tumor necrosis factor-α (TNFα) therapies) will in most cases address the joint pain associated with rheumatoid arthritis. Not all inflammatory pain states can be treated with such therapies and most non-inflammatory pains (e.g. neuropathy, cancer pain) has either no clear underlying disease state or the treatment itself can induce pain-causing pathology (e.g. chemotherapy-induced pain). Persistent pain associated with injury or diseases (such as diabetes, arthritis, or cancer) can result from damage to nerve fibers, leading to increased conduction or neurotransmitters. The reader is referred to recent reviews on molecular mechanisms of pain in general or specific pain types [3-5] There are at least three main classes of drugs used to treat pain: 1) the non-steroidal anti-inflammatory drugs (NSAIDs or coxibs) - examples include naproxen, diclofenec and celecoxib - generally for mild-to-moderate inflammatory pain; 2) narcotic analgesics - examples include morphine, oxycodone and buprenorphine - for moderate-to-severe pain including cancer pain and neuropathic pain; and 3) the non-traditional analgesics (antidepressants and anticonvulsants) - mainly for neuropathic pain. Inflammatory nociceptive pain is associated with inflammation and tissue damage. Cytokines (TNFα, interleukins 1 and 6) are often elevated resulting in accumulation of inflammatory cells. Cyclooxygenase (COX), an enzyme required for the synthesis of prostaglandins, is elevated in response to cytokines [5]. Prostaglandins produced by COX cause inflammation and pain. All NSAIDs exhibit a similar mechanism of action, i.e., COX activity. Although effective on mild-to-moderate pain, gastrointestinal (GI) ulcerations are the major problem with traditional NSAIDs that inhibit both COX-1 and COX-2 [6]. Although COX-2 inhibitors offer a better GI safety profile, between 2004 and 2005 two of the available COX-2 inhibitors, rofecoxib (Vioxx, Merck & Co) and valdecoxib (Bextra, Pfizer) were withdrawn from the market due to an increased risk of adverse cardiovascular events [7]. Celecoxib (Celebrex, Pfizer) is still available for use, but should be used with extreme caution in patients with existing cardiovascular (CV) disease. Currently aspirin and naproxen are the only NSAIDs that are either CV protective (aspirin) or with minimal adverse CV effects (naproxen). Naproxen is a relatively more potent analgesic; however, both drugs suffer from serious GI issues. Several companies are working on improving the GI/CV profile of naproxen and other drugs. NiCox is developing a nitric oxide donating version of naproxen (Naproxcinod) for pain associated with osteoarthritis. Although it appears to have some hypotensive effect [8], its overall CV benefits remain to be proven, and it was recently rejected by the FDA panel. Logical Therapeutics is developing its investigational drug LT-NS001 (naproxen etemesil, in Phase 2), which is pharmacologically inactive in the GI tract, but once absorbed into the bloodstream is converted to naproxen. Opioids are the most commonly prescribed and perhaps most effective medications for pain. It is estimated that 90% of patients presenting to pain centers and receiving treatment in those facilities are on opioids [9, 10]. Opioids can be considered broad-spectrum analgesics that act at multiple points along the pain pathway. Opioids, which are generally prescribed for moderate-to-severe pain (cancer/non-cancer pain, back pain and breakthrough pain), are agonists, mixed agonists-antagonists, or partial agonists for opioid receptors [11-13]. Opioids achieve their analgesia through their interaction primarily with the mu and kappa opioid receptors. There is some evidence that these agents also act at delta opioid receptors. The mu receptor has been identified in the neural tissue of areas that are part of the body's descending pain pathway. Opioids' activity at these receptors also mediates their adverse effects i.e., euphoria, respiratory depression and constipation [10]. The kappa receptor mediates sedation. The delta receptor mediates dysphoria and psychomimetic effects. Other common adverse effects of opioid use include urinary retention, orthostatic hypotension, nausea and vomiting. Another major issue often encountered with long-term use of opioid therapy is the development of tolerance - defined as the failure of a steady dose of the drug to sustain the desired pharmacological effect over time, i.e., the need to increase drug dose to maintain the desired pharmacological effect. Opioid use in neuropathic pain is often limited by the development of analgesic tolerance. In addition, sustained use sometimes leads to the development of hyperalgesia - dramatically increased sensitivity to painful stimuli. Inflammation and inflammatory cytokines appear to be key players contributing to the development of tolerance and hyperalgesia [14]..........

Opioid analgesics are the most frequently prescribed medications for the treatment of moderate or severe pain; however, their use is constrained by unwanted side effects. One therapeutic approach used to improve the side effect profile of opioids is the administration of a second drug in an opioid-containing mixture. Preclinical studies designed to predict the therapeutic potential of novel opioid-containing drug combinations are currently underway, and must rely on quantitative methods to assess their interactive effects. In this manuscript, an overview of isobolographic analysis is presented along with recent advances in isobolographic theory pertaining to drugs that differ in efficacy and to the statistical analysis of dose-addition. Next, studies using these analyses to assess the interactive effects of opioids and novel adjunct drugs, including selective COX-2 inhibitors, α2-adrenergic receptor agonists, δopioids, glutamate receptor antagonists and cannabinoid receptor agonists, are reviewed. Finally, comments on the future assessment of drug combinations for the treatment of pain-related disorders are made.

Cannabinoids are antinociceptive in animal models of acute pain, tissue injury and nerve injury induced nociception and act via their cognate receptors, cannabinoid receptor 1 and 2. This review examines the underlying biology of the endocannabinoids and behavioural, neurophysiological, neuroanatomical evidence supporting the notion of pain modulation by these ligands with a focus on the current evidence encompassing the pharmacological characterization of CB1 agonists in this therapy. Separating the psychotropic effects of CB1 agonists from their therapeutic benefits is the major challenge facing researchers in the field today and with the discovery of peripherally acting agonists there seems to be a ray of hope emerging for the diverse potential therapeutic applications of this class of ligands.

Fatty acid amide hydrolase (FAAH) is responsible for hydrolysis of endocannabinoid, anandamide (AEA), and N-acyl ethanolamines such as palmitoylethanolamine (PEA) and N-oleoylethanolamide (OEA). Genetic deletion or pharmacological inactivation of FAAH shows site-specific elevation of AEA that plays a role in the modulation of pain and other neurodegenerative disorders. The review elaborates recent progress and current status of diverse structural classes of reversible and irreversible FAAH inhibitors. The discussion also addresses ligand-enzyme active site interactions and mechanism of enzyme inactivation, emerging approaches to novel FAAH inhibitors, and ongoing efforts to address gaps in therapeutic utility of FAAH inhibitors.

Neuropathic pain is a compilation of somatosensory, cognitive and emotional alterations developing following nerve injuries. Such pain often outlasts the initial cause and becomes a disease of its own that challenges its management. The actions of currently used anticonvulsants, antidepressants and opioids are hampered by serious central nervous system adverse effects, which preclude their sufficient dosing and long-term use. Conversely, selective activation of opioid receptors on peripheral sensory neurons has the advantage of pain relieve without central side effects. Considerable number of animal studies supports analgesic effects of exogenously applied opioids acting at peripheral opioid receptors in neuropathic conditions. In contrast to currently highlighted pain-promoting properties of neuroimmune interactions associated with neuropathy, recent findings suggest that opioid peptide-containing immune cells that accumulate at damaged nerves can also locally alleviate pain. Future aims include the exploration of opioid receptor signaling in injured nerves and of leukocytic opioid receptor function in pain modulation, development of approaches selectively delivering opioids and opioid-containing cells to injured tissues and investigation of interactions between exogenous and leukocyte-derived opioids. These efforts should lay a foundation for efficient and safe control of neuropathic pain. This article comprehensively analyzes the consequences of nerve injury on the expression of peripheral opioid receptors and peptides, and the impact of these changes on opioid analgesia, critically discussing positive and negative findings. Further focus is on a dual character of immune responses in the control of painful neuropathies.

Interleukin-1β (IL-1β) has been implicated in many inflammatory and autoimmune diseases. Its role in pain, however, is under-appreciated. This may in part be due to the challenges involved in approaching the target from a therapeutic stand point. The scope of this brief review is to understand the direct and indirect roles of IL-1β in contributing to different pain states including inflammatory and neuropathic pain, and discuss approaches to block IL-1β production or IL-1&bgr-receptor interactions.

Most of the newly developed drugs fails to achieve sufficient bioavailability in to brain due to low water solubility and low permeability. Drug delivery systems are one method for achieving entry of molecules to their desired site of action within the body. Dendrimers are the customizable nanopolymers with uniform and well-defined particle size and shape. Dendrimers are of eminent interest for biomedical applications because of their ability to cross cell membranes. This potential pharmaceutical delivery system crosses the blood brain barrier (BBB) and other important target points. The high level of control over the dendritic architecture (size, branching density, surface functionality) make dendrimers ideal carriers in the field of brain drug delivery of anticancer, antiinflammatory, and antimicrobial agents. Examples of dendrimers such as poly(amidoamine) (PAMAM), poly(propylene imine) (PPI) and polyether-copolyester (PEPE), Glyco, PEGylated, peptide and pH dendrimers are of outmost significance. These dendrimers carriy the drug molecules by physical interactions (encapsulation) or through chemical bonding (prodrug approach), while pH sensitive dendrimers are able to deliver drug molecules by alteration of ionic exchange in the brain microenvironment at the tumor site. Techniques employing dendrimers could be especially useful for drugs targeting to Alzheimer's and Prion's diseases. The present review should be of value to scientists who wish to work on the dendrimers for the delivery of molecules into the brain by systemic dosing.

Neuropathic pain is a debilitating form of treatment resistant chronic pain and responds poorly to the clinically available therapies. Studies from animal models of neuropathic pain have led to understanding of its pathobiology which includes complex interrelated pathways leading to peripheral and central neuronal sensitization. Advancements in the elucidation of neuropathic pain mechanisms have revealed a number of key targets that have been hypothesized to modulate clinical status. The present review discusses these therapeutic targets including noradrenaline and 5-HT reuptake inhibitors; sodium, calcium and potassium channels; inhibitory and excitatory neurotransmitters; neuropeptides including bradykinin, tachykinin, cholecystokinin, neuropeptide Y, vasoactive intestinal peptide, and CGRP; pro-inflammatory cytokines; MAP kinases; PPAR γ; Na+/Ca2+ exchanger; nitric oxide; purinergic receptors; neuronal nicotinic receptors; cation-dependent chloride transporters; oxidative stress; matrix metalloproteinase and plasminogen activators; growth factors; transient receptor potential (TRP) channels; endocannabinoids; histamine receptors; dopamine; sigma receptors, beta adrenergic receptors, endothelins, and D-amino acid oxidase. The exploitation of these targets may provide effective therapeutic agents for the management of peripheral nerve injury-induced neuropathic pain.

Unlike for depression, only few studies are available today investigating the therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) for anxiety disorders. This review aims to provide information on the current research approaches and main findings regarding the therapeutic use of rTMS in the context of various anxiety disorders. Although positive results have frequently been reported in both open and randomized controlled studies, our review of all identified studies indicates that at present no conclusive evidence of the efficacy of rTMS for the treatment for anxiety disorders is provided. Several treatment parameters have been used, making the interpretation of the results difficult. Moreover, sham-controlled research has often been unable to distinguish between response to rTMS and sham treatment. However, there is a limitation in the rTMS methods that likely impacts only the superficial cortical layers. It is not possible to directly stimulate more distant cortical areas, and also subcortical areas, relevant to the pathogenesis of anxiety disorders, though such effects in subcortical areas are thought to be indirect, via trans-synaptic connections. We thus recommend further studies to clearly determine the role of rTMS in the treatment of anxiety disorders. Key advances in combining TMS with neuroimaging technology may aid in such future developments.

Neuroinflammation is considered a chronic activation of the immune response in the central nervous system (CNS) in response to different injuries. This brain immune activation results in various events: circulating immune cells infiltrate the CNS; resident cells are activated; and pro-inflammatory mediators produced and released induce neuroinflammatory brain disease. The effect of immune diffusible mediators on synaptic plasticity might result in CNS dysfunction during neuroinflammatory brain diseases. The CNS dysfunction may induce several human pathological conditions associated with both cognitive impairment and a variable degree of neuroinflammation. Furthermore, age has a powerful effect on enhanced susceptibility to neurodegenerative diseases and age-dependent enhanced neuroinflammatory processes may play an important role in toxin generation that causes death or dysfunction of neurons in neurodegenerative diseases This review will address current understanding of the relationship between ageing, neuroinflammation and neurodegenerative disease by focusing on the principal mechanisms by which the immune system influences the brain plastic phenomena. Also, the present review considers the principal human neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis and psychiatric disorders caused by aging and neuroinflammation.

The neurotrophin Nerve Growth Factor (NGF) is essential for the maintenance and differentiation of basal forebrain cholinergic neurons. Since basal forebrain cholinergic neurons represent one major neuronal population affected and progressively degenerating in Alzheimer's disease (AD), interest has grown for NGF as a potential therapeutic agent in neurodegenerative disorders linked to aging, particularly for AD. However, no evidence was available, to link, in a cause-effect manner, deficits in NGF signalling to the broader activation in the Alzheimer's cascade, besides cholinergic deficits. The phenotypic analysis of the AD11 anti-NGF transgenic mouse, obtained by the “neuroantibodies” phenotypic protein knock out strategy, allowed demonstrating a direct causal link between NGF deprivation and AD pathology. Since then, extensive mechanistic studies on the AD11 model provided a new twist to the concept that alterations in NGF transport and signalling play a crucial role in sporadic Alzheimer's neurodegeneration, leading to the hypothesis of “neurotrophic imbalance” as an upstream driver for sporadic AD. The results obtained with the AD11 anti-NGF mice highlight the fact that the particular mode of NGF neutralization, with an NGF antibody expressed in the brain, selectively interfering with mature NGF versus unprocessed proNGF, plays a major role in the mechanism of neurodegeneration, and could lead to new insights into the mechanisms of human sporadic AD. Here, we will review (1) the renewed neurotrophic imbalance hypothesis for AD and (2) the mechanisms underlying the neurodegenerative phenotype of AD11 anti-NGF mice.