Current Medicinal Chemistry - Central Nervous System Agents - Volume 3, Issue 4, 2003

Mitochondrial defects have been linked to such devastating neurodegenerative diseases as Parkinson's, Huntington's, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Alzheimer's as well as senile dementia's. Mitochondrial metabolic defects could affect the electron transport, the tricarboxylic acid cycle (TCA), and substrate transport. However, it is the escape of oxygen free radicals (superoxide formation) as a result of a disturbed electron transfer within the respiratory chain that is thought to underlie many of the deleterious effects of mitochondrial dysfunction. A therapeutic strategy aimed at ameliorating these effects with supplementation of antioxidants, cofactors, and substrates is becoming prevalent. L-carnitine (LC), a biologically active stereoisomer of trimethylammonium hydroxide, is a highly polar, small zwitterion (inner salt). Ingested, LC is incorporated into the total body carnitine pool that includes unchanged LC, acetyl-L-carnitine (ALC), and other carnitine esters. LC optimises cell energy production by transporting medium and long chain fatty acids into the mitochondria for utilization in metabolism through β-oxidation. Free LC serves then two important intra-mitochondrial functions. It maintains the acetyl-CoA / CoA ratio and scavenges excess potentially toxic, free acyl groups to transport them out of the mitochondria. A lower acetyl-CoA / CoA ratio favors the action of pyruvate dehydrogenase that increases the formation of acetyl-CoA from pyruvate. The increased formation of acetyl-CoA from pyruvate significantly impacts glucose oxidative metabolism by limiting access to the TCA cycle. LC is also important in maintaining cell membrane stability through its involvement in acetylation of membrane phospholipids and amphiphilic actions. The carnitine system plays a role in the mitochondrial elongation-desaturation of the ω-3-polyunsaturated fatty acids to docosahexaenoic acid (DHA). Thus, LC is an endogenous mitochondriotropic substance and its use in therapy is to replace depleted carnitine levels, resulting in restoration of normal cellular and, hence body functions. LC and its acetylated form, acetyl-L-carnitine (ALC), may have antioxidative properties, protecting cells against lipid peroxidation and membrane breakdown. The carnitine system prevents loss of mitochondrial function in isolated liver mitochondria, prevents lipid peroxidation damage associated with energy loss due to hypobaric hypoxia in rat brain cells, and protects against mitochondrial inhibitor-induced toxicity in neurons. Consequently, LC protects against the neurotoxicity induced by mitochondrial inhibitors such as 3-nitropropionic acid (3-NPA) as well as methamphetamine. Supportive findings indicating a protective ability of LC and some of its esters at the mitochondrial level in the CNS have been reported by various groups and are discussed in further detail in this review.

The escalating pandemic of obesity has generated demand for a new generation of novel anti-obesity agents. Over the past 8 years numerous systems within the CNS critical to the expression of appetite and energy regulation have been revealed. With increasing knowledge we seem tantalisingly close to producing an unprecedented range of anorectic agents capable of inducing sustained clinical weight loss. However, it remains essential to establish that any test compound reduces food intake by selectively acting on the endogenous appetite system (or by inducing nausea or malaise). Only drugs (agonist or antagonist) that modify the daily flux of appetite, for instance enhancing within meal satiation and strengthening post meal satiety, can be considered as appetite suppressants with clinical potential. Systems of interest include peripheral factors released episodically prior to, during and after the consumption of food, many of which have been shown to have receptors within the Central Nervous System (CNS). These include Glucagon-Like Peptide (GLP)-1, Cholecystokinin (CCK), Gastrin Releasing Peptides (GRP), Enterostatin, Amylin, Peptide YY (PYY) and most recently Ghrelin. The identification of the hormone leptin (the ob protein), a key signal linking adipose tissue status with key CNS regulatory circuits, was arguably the key event in the current revolution in appetite research. Leptin itself may be one of a much larger class of peripheral tonic signals, with receptors within the CNS, informing the brain of the body's energy status and providing a second set of target systems. Collectively, these episodic and tonic signals appear to be integrated in key CNS circuits containing monoamine neurotransmitters (Serotonin - 5-HT, Nor-Adrenaline - NA, and Dopamine - DA) and numerous neuropeptides (Melanocortins, Neuropeptide Y - NPY, Orexins, Cocaine and Amphetamine Regulating Transcript - CART, Agouti Related Peptide - AgRP and Galanin) all of which could be selectively targeted to reduce food intake and induce weight loss. Food intake can also be adjusted by drugs such as the cannabiniods acting upon the hedonic components of eating behaviour. However, any drug targeting the aforementioned systems must produce changes in feeding behaviour such as meal patterns and food choice consistent with a selective action on appetite. Ultimately in humans, this will be expressed in changes in meal size, reduced snacking and possibly a selective reduction in the intake of calorie dense high fat foods.

In the 1950s, the first antidepressant drugs, the tricyclic antidepressant (TCA) imipramine and the monoamine oxidase inhibitor (MAOI) iproniazid, were introduced. However, these drugs had 3 particular drawbacks. Firstly, a lag time of several weeks before clinically therapeutic effects was observed. Secondly, the agents were only effective in relieving symptoms in approximately two-thirds of patients. Thirdly, due to their non-selective nature, they were associated with a variety of unpleasant and in some cases fatal adverse effects. The more recently introduced drugs have an improved safety profile, but not a quicker onset or more effective. New targets have emerged as a consequence of our increasing knowledge of the neurochemical, endocrine and immunological changes associated with depression. Study of the hypothalamic-pituitary-adrenal (HPA) axis has resulted in the development of corticotrophin releasing hormone (CRH) antagonists, glucocorticoid synthesis inhibitors and glucocorticoid receptor antagonists. Neuropeptide targets have included neuropeptide Y (NPY) and neurokinin (NK) receptors. Alterations in immune function in depression have led to the proposal that cytokines may hold the key. Reinvestigating the process of monoamine neurotransmission has largely centred on the serotonergic system, as well as the NMDA receptor, and intracellular signalling mechanisms. The most developed of these approaches at present are those associated with the serotonergic, HPA axis and neuropeptide targets. The plethora of targets and the sustained development of chemical entities with greater selectivity and bioavailability provide the hope that these approaches will result in the development of antidepressants with truly novel mechanisms of action.

N-Methyl-D-aspartate (NMDA) receptor (NR) antagonists have contributed to the major advances in research of excitatory synaptic transmission, neuronal excitotoxicity, and neurodegenerative disorders. Activation of the NRs evokes a rapid Ca2+ influx into neurons, resulting in an activation of a variety of intracellular signal cascades, Ca2+ mobilization, and alterations in membrane channel activity and gene expression. The signal transduction mechanisms play a fundamental role in how the brain functions physiologically but are also at the core of neural injury and dysfunction. Evidence is emerging that abnormal NR activation underlies the development of depressive symptoms and of many forms of dementia. Correcting abnormal activity of the NRs thus represents an attractive and essential therapeutic strategy in antidepressant and antidementia medications. NR antagonism can be achieved pharmacologically through blocking the NR / complex at its various binding sites, including the NR glutamate-binding site, the ion channel binding site, the glycine co-agonist site, the polyamine binding site, and the redox modulatory site(s). Agents that have antagonistic activity at the different sites show differential structure-activity relationships, possess distinct pharmacological profiles, and therefore have different therapeutic potentials. This review summarizes current knowledge and developments concerning a variety of NR antagonists and discusses their potential as pharmacological drugs in the treatments of depression and dementia.

Lithium, which has been used in the psychiatric domain for many years, is showing interesting properties as a neuroprotective agent against different apoptotic insults. These neuroprotective effects have been explained by its action in signaling pathways implicated in apoptosis and cell survival. Studying the action of lithium in these signaling pathways, emerging data show lithium as an inhibitor of the dephosphorylation events. The importance of phosphorylation and dephosphorylation in intracellular signaling pathways has been long recognized, although attention has focused mainly on kinases, which have become the second most important group of drug targets. However, recent studies are highlighting the importance of serine / threonine protein phosphatases in apoptosis. The effect of lithium on serine / threonine protein phosphatases needs further study, but lithium is pointing out these enzymes as potential targets for novel therapeutics against neurodegenerative diseases.

Protein kinases (PKs) mediate neuronal morphology, differentiation, survival, repair, and plasticity in central nervous system (CNS). In this review, the structure and function of PKs involved in CNS function, various neurological disorders, learning process, and memory are discussed. Certain types of PKs and their ligands have been implicated in memory and learning, axon guidance, the formation of neural projections, axon fasciculation, cell migration, and neurotrophin signaling. Many of these functions are regulated via the action of protein tyrosine kinases (PTKs) and their ligands, such as epidermal growth factor (EGF) receptor, Janus kinase-signal transducer and activator of transcription (JAK / STAT), Fyn-tyrosine kinase, Eph receptors, and neurotrophins (NTs) [e.g., brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF)]. Serine / threonine kinases, such as activins, bone morphogenic proteins (BMPs), mitogen-activated protein (MAP) kinases (e.g., p44 / 42 MAPK, c-Jun N-terminal kinase, p38 MAPKs), and protein kinases A (PKA) and C (PKC) and their function in the CNS are also discussed. The role of protein kinase inhibitors (PKIs), isolated from microbial, botanical sources or synthesized by conventional approaches, in determining CNS signaling cascades and function, and the treatment of neurological disorders is reviewed.