Current Drug Targets-CNS & Neurological Disorders - Volume 1, Issue 6, 2002

Galanin is a biologically active neuropeptide, widely distributed in the central and peripheral nervous systems and the endocrine system. The amino acid sequence of galanin is very conserved (almost 90%among species), indicating the importance of the molecule. Galanin has multiple biological effects. In the central nervous system, galanin alters the release of several neurotransmitters. In particular the ability of galanin to inhibit acetylcholine release, along with the observation of hyperinervation of galanin fibres in the human basal forebrain of Alzheimer's disease patients, suggest a possible role for galanin in the cholinergic dysfunction, characteristic of the disease. Moreover, galanin has been suggested to be involved in other neuronal functions, such as learning and memory, epileptic activity, nociception, spinal reflexes and feeding. Galanin has also been shown to increase the levels of growth hormone, prolactin and luteinizing hormone, to nhibit glucose induced insulin release and to affect gastrointestinal motility. The expression of galanin (mRNA and peptide levels) is elevated following estrogen administration, neuronal activation, denervation and / or nerve injury, as well as during development. The spectrum of galanin's activities indicates that galanin is an important messenger for intercellular communication within the nervous system and the neuroendocrine axis. Galanin acts at specific membrane receptors to exert its effects, so far three human and rodent galanin receptor subtypes have been cloned. Galanin agonists have been shown to have therapeutic application in treatment of chronic pain, galanin antagonists have therapeutic potential in treatment of Alzheimer's disease, depression, and feeding disorders.

The endothelin system, consisting of three peptides, two peptidases and two G-protein coupled receptors, is widely expressed in the brain cell types and brain-derived tumor cell lines. The stimulation of endothelin receptors elicits a variety of short- and long-term changes at cellular level but the effects of the modulation of the endothelin system in brain physiology and pathophysiology are, at the present time, poorly understood. Altered expression of endothelins (ETs) in reactive astrocytes has been observed in many pathological conditions of the human brain, such as infarcts, lacunae, traumatic conditions, Alzheimer's disease and inflammatory diseases of the brain. In addition, recent studies have shown that endothelin antagonists might inhibit growth and induce cell death in human melanoma cells in vitro and in vivo, and have emphasized a possible role of endothelin peptides as autocrine or paracrine factor in the proliferation and dissemination of tumor cell lines. Given the fact that brain cell and a variety of brain tumor cell lines express all the components of the endothelin system, further studies are warranted to demonstrate a possible therapeutic role of endothelin antagonist in the pharmacological treatment of brain diseases and brain tumors.

The mammalian circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus conveys 24-hr rhythmicity to sleep-wake cycles, temperature, locomotor activity and virtually all other behavioral and physiological processes. In order for these cycles to be adaptive, they must be synchronized, or entrained, to the 24-hr light / dark cycle produced by the rotation of the Earth. The timing of circadian variables relative to the light / dark cycle, i.e., the phase angle of entrainment, is influenced by intrinsic circadian clock properties that are to an extent genetically determined, and thus varies between individuals. In extreme cases (advanced or delayed sleep phase syndrome) or during shift work or jet lag, the phase angle of entrainment may be incompatible with work requirements or other social demands, resulting in negative consequences to health and productivity. This review describes the etiology of circadian disorders within the context of formal circadian clock properties and summarizes studies in humans and in other species which link specific genetic loci to circadian clock function and malfunction. The proteins encoded by these genetic loci play key roles in the intracellular feedback loop that generates circadian rhythms, and thus represent therapeutic targets for the treatment of both endogenous and exogenous circadian disorders.

The plasma membrane has been the subject of intense investigation in the search for antiamyloidogenic drugs for the treatment of Alzheimer's disease. Studies have highlighted numerous toxic properties of the well-known amyloid Aβ peptide on neuronal membranes. In this respect recent experimental data suggest that an early step in amyloid toxicity might be intracellularly mediated. This suggests that effective anti-amyloidogenic agents must be able to readily cross the plasma membrane while at the same time, counteracting the deleterious effects of the Aβ peptide on the phospholipid bilayer. This review summarizes recent findings regarding amyloid-plasma membrane interactions and discusses their relevance for the design of novel, potential anti-Aβ drugs.

A body of evidence emerging in antidepressant and antidementia research has revealed a convergence of molecular events known to regulate neuronal plasticity in learning and memory with molecular actions of drugs for the treatment of depression. Many antidepressants are reported to have positive impact on learning and memory. These include agents acting through monoaminergic neurotransmitter systems, non-monoaminergic transmitter systems, and hormones. On the other hand, agents that appear to have memory-enhancing or antidementia value are frequently found to exhibit antidepressant activity in patients and animal depression models. It is becoming clear that the comorbidity of depression and dementia does not occur by chance, but rather is an inevitable consequence of pathologic relationships between the conditions. Molecular mechanisms and cascades that underlie memory may be shared by mood regulation and are vulnerable to stress and injuries. This review focuses on recent findings regarding effects of a variety of agents on dementia and depression and their common molecular mechanisms as well as their differences. A better understanding of the key underlying molecular components whose changed activities have dramatic influences on mood and cognition may lead to the development of novel and more effective therapeutic agents for the treatment of depression and dementia. In this review, some of the recent findings that suggest novel therapeutic strategies are also highlighted.

This review discusses the current understanding of organophosphate induced delayed polyneuropathy (OPIDP) with emphasis on molecular mechanisms, pathogenesis and possibilities for prevention / therapy. OPIDP is a rare toxicity caused by certain organophosphorus compounds (OP) characterized by degeneration of some long axons in the central and peripheral nervous system that appear about 2-3 weeks after exposure. The molecular target for OPIDP is considered to be an enzyme in the nervous system known as neuropathy target esterase (NTE). NTE can be inhibited by two types of inhibitors: a) phosphates, phosphonates, and phosphoramidates, which cause OPIDP when >70% of the enzyme is inhibited, and b) phosphinates, carbamates, and sulfonyl halides which inhibit NTE and cause either protection from, or promotion, of OPIDP when given before or after a neuropathic OP, respectively. The ability of a NTE inhibitor to cause OPIDP, besides its affinity for the enzyme, is related to its chemical structure and the residue left attached to the NTE. If such residues undergo the aging reaction i.e. the loss of an alkyl group bound to the enzyme, those OPs usually have a high likelihood of causing OPIDP. Protection from neuropathic doses of OP inhibitors is obtained when NTE is inhibited with nonageable inhibitors. Promotion of OPIDP involves another site besides NTE because it can occur when all NTE is affected. It is now known that this other site is similar to NTE in that it is also sensitive to mipafox but at much higher concentrations. Promotion affects either the progression or expression of OPIDP after the initial biochemical effect on NTE. Some recent observations suggest that development of OPIDP in hens can be influenced by atropine, oximes and methylprednisolone when they are given before or soon after neuropathic OPs.