=============================================================== == -- ALS INTEREST GROUP -- == == ALS DIGEST (#18, 05 FEB 1993) == == To subscribe, unsubscribe, or to contribute notes, please == == send e-mail to bro@huey.met.fsu.edu (Bob Broedel). == =============================================================== Date : Wed, 3 Feb 1993 21:18:20 +0100 Sender : "Neuroscience Information Forum" > From : Paul.Herrling@PKFLTG.PHARMA.SANDOZ.CH Subject: ALS To : Bob Broedel Dear Bob, As promised some info on possible emerging therapies from research on excitatory amino acids. You will find a section in the review article below. Some compounds developed according to the EAA hypothesis are now in clinical testing for neurotoxicity indications, however, I am not sure if ALS is addressed specifically. Kind regards -Paul Herrling The NMDA Receptor, Editors J.C. Watkins, G. Collingridge IRL-Press 1993 (in press) Chapter XX "Clinical implications of NMDA receptors" PAUL L. HERRLING A) INTRODUCTION In the past the major clinical applications of chemical therapeutic agents were frequently first discovered in the clinic following their introduction in another area and before their mechanism of action was known in any detail, e.g. chlorpromazine was first used as a sedative to potentiate anesthesia (Laborit et al. 1952) before its antipsychotic potential was discovered (Delay et al. 1952). In the field of excitatory amino acids a different trend seems to prevail. The discovery of such agents about thirty years ago led, after alternating periods of scepticism and enthusiasm (Watkins 1988) concerning their role as major excitatory transmitters in the mammalian central nervous system, to the recent explosion of publications, particularly on N-methyl-D-aspartate (NMDA; The Scientist 1989). These studies on the physiology and pharmacology of excitatory amino acids led to a new understanding of the high degree of complexity of excitatory transmission in the brain, far removed from the early concept that postsynaptic depolarization caused excitation and hyperpolarization inhibition. As a consequence of this recent knowledge, workers in the field have proposed therapeutic applications for drugs modulating excitatory amino acid systems, ranging across the entire field of psychiatry and neurology, although only a very limited number of such compounds have reached the stage of clinical evaluation. This review will attempt a summary of the proposed therapeutic applications for drugs modulating excitatory amino acids and a short description of the rationale which led to these proposals. The emphasis will be on NMDA modulating compounds, but mention will also be made of possible clinical applications for compounds acting at non-NMDA receptors. B) THERAPEUTIC APPLICATIONS FOR DRUGS MODULATING EXCITATORY AMINO ACID SYSTEMS a) Anticonvulsive therapy One of the earliest observations relating to application of glutamate and aspartate to the mammalian brain was their ability to cause convulsions (Hayashi 1954). More recently the view that excessive activity of excitatory amino acid transmission might be the cause of epileptic episodes was further strengthened by the observation that NMDA receptor agonists can induce cells to fire in rhythmic bursts in several brain regions including the cortex, hippocampus and caudate nucleus as reviewed by Meldrum (1985). It was therefore proposed that anticonvulsant therapy in man might be achieved by the use of antagonists of the NMDA receptor complex. This approach was predominantly pursued by Meldrum and colleagues using a wide range of animal models, including primates (1985, 1987). Interestingly, antagonists of the NMDA receptor, both of the competitive type, such as 2-amino-7-phosphonoheptanoate (AP7) (Meldrum 1986) and 3-((n)-2-carboxypiperazin-4-yl)-propyl-1-phosphonate (CPP) (Davies et al. 1986) as well as NMDA channel blockers like dizocilpine (MK-801) (Meldrum 1988) all display anticonvulsant properties in animal models of epilepsy. MK-801 also reduces the frequency of convulsive episodes in man (Troupin et al. 1986). Non-NMDA antagonists such as 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX: FG9065) do not seem to be as effective in some models of epilepsy (Jensen and Sheardown 1988). The potential treatment of high pressure neurological syndrome (HPNS) by NMDA antagonists has also been investigated. A relatively selective and competitive NMDA antagonist, AP7, is able to more than double the atmospheric pressure at which tremor occurs in HPNS and also protects against pressure-induced myoclonus and convulsions (Meldrum et al. 1983). Drugs with such properties might be useful whenever work at high pressure, such as in the deep-sea environment, is required. b) Neuroprotection Selective destruction of neuronal cell bodies in the CNS with sparing of passing axons and glial cells can be achieved by local or in some cases also systemic application of excitatory amino acid agonists (Lucas and Newhouse 1957, Rothman and Olney 1987). This property of excitatory amino acids led to the widespread experimental use of agents like kainate, ibotenate, quinolinate etc. as tools in neurobiology whenever selective neuronal destruction was required (Fuxe et al. 1983). Such excitotoxic properties which are shared by excitatory amino acids endogenous to the mammalian brain were also the basis of several hypotheses relating to the causation of certain neurodegenerative diseases (Albers et al. 1989, Choi 1990). Thus, clinical syndromes in which selective premature neuronal death occurs might at least in some cases be due to excessive activation of excitatory amino acid systems, resulting from pathologically increased release and/or decrease of uptake. Alternatively, exogenous excitotoxins occurring in the environment might be responsible for such symptoms. Hypoxic/ischemic damage to the central nervous system. Exposure of mammalian brain tissue in cultures to hypoxic episodes results in progressive neuronal deterioration and death. Rothman (1984) demonstrated that this neuronal death could be partly prevented in vitro by applying the broad-spectrum excitatory amino acid antagonist -D-glutamylglycine to cultures during hypoxic episodes. Intrahippocampal injections of the competitive NMDA antagonist, AP7, in rats reduced hippocampal neuronal damage following experimental forebrain ischemia (Simon et al. 1984). NMDA channel blockers such as MK-801 were also shown to reduce the volume of neuronal damage due to middle cerebral artery occlusion in cats (Ozyurt et al. 1988). Similar findings were obtained in rats with a non-competitive NMDA antagonist of unknown mechanism, ifenprodil (Gotti 1988) (see Chapter 17 [?]) and in cats with competitive NMDA antagonists such as D-CPP-ene (SDZ EAA 494) (Bullock et al. 1990). Recently, additional evidence has accumulated suggesting a excitotoxic role of NMDA receptors in spinal cord injury (Faden et al. 1990, Liu et al. 1991), in perinatal hypoxic conditions (Kjellmer 1991, Young et al. 1990) and concussive brain injury (Katayama et al. 1990). It was therefore proposed that excitatory amino acids interacting with the NMDA system might be responsible for neuronal death following hypoxic/ischemic conditions, possibly also in man, due to their selective neurotoxic properties (Choi 1990). Clinical studies might be planned to evaluate the effects of drugs inhibiting the NMDA system in stroke, head injury and post-cardiac arrest. An important feature of these studies will be to determine if a beneficial effect of such drugs can be demonstrated even when applied several hours after the occurrence of the injury, as in normal clinical practice some time usually elapses before patients are diagnosed and treatment can begin. Preliminary animal studies indicate that post-injury treatment with NMDA antagonists might still protective effects (Woodruff et al. 1988). Endogenous neurotoxins. Some compounds endogenous to the human brain such as the tryptophan metabolite quinolinic acid, a selective NMDA agonist in some parts of the brain, have been shown to be neurotoxic (Stone et al. 1987).The group around Schwarcz (Schwarcz et al. 1983) has performed a series of elegant studies aimed at elucidating the metabolism and distribution of quinolinic acid in the mammalian brain, including man (Schwarcz et al. 1983,). As it appears that quinolinic acid is not released upon depolarization of neurons and does not have a specific uptake system it is unlikely to be a neurotransmitter in the mammalian brain. However, Schwarcz and colleagues have hypothesised that it might be released under pathological conditions (Schwarcz et al. 1988a,b; Freese et al. 1990). Furthermore, they showed that there is only an intracellular metabolic mechanism for this agent; there is no extracellular inactivation mechanism for quinolinic acid except for diffusion. Upon its release it might therefore cause neurotoxic damage (Whetsell et al. 1988) in such conditions as Huntington's disease or in hepatic encephalopathy, as suggested by Moroni and colleagues (1986). Amyotrophic lateral sclerosis is another degenerative disease with selective neuronal death where an abnormality of endogenous excitatory amino acids has been implicated (Allaoua et al. 1992, Perry et al. 1990, Rothstein 1990, Plaitakis 1990), in addition to the possible involvement of exogenous excitotoxins (see below). Because NMDA-antagonists provoke release of dopamine in basal ganglia (Imperato et al. 1990) and because they cause monoamine-like locomotor stimulation in monoamine-depleted rodents it was proposed (Carlsson and Carlsson 1990, Greenamyre and O'Brien 1991, Svensson et al. 1991) that NMDA antagonists could be useful agents in Parkinson's disease. Furthermore, these agents protect substantia nigra neurons from MPP+ toxicity in animals (Turski et al. 1991, Turski and Stephens 1992) and potentiate the effects of L-DOPA in monoamine-depleted rats (Klockgether and Turski 1990). Exogenous excitotoxins. Amyotrophic lateral sclerosis, Alzheimer-type dementia and Parkinsonism are all syndromes where post-mortem investigations reveal neuronal death in discrete areas: neurons in cortex and the spinal cord, cholinergic cells of the basal forebrain and dopamine cells of the substantia nigra, respectively. These findings are similar to those obtained by injecting excitotoxins in the same regions in animal models and therefore the involvement of environmental excitotoxins in their etiology has been investigated by several groups. In the 1950s the Chamorro population of Guam and Rota in the western Pacific exhibited an incidence of symptoms usually associated with the diseases described above that was 50 to 100 times higher than in the continental U.S. Meanwhile, the incidence has declined, inducing researchers to look for an environmental change to account for this phenomenon (Spencer et al. 1987a). Suspicion focussed on compounds found in the seed of Cycas circinalis (false sago palm) which was used as food-source until after the war on these islands. Spencer and his colleagues (1987b) isolated amongst others -N-methylamino-L-alanine (BMAA) and characterized it as a possible excitotoxic agent, responsible for the neurodegenerative symptoms. However, the hypothesis is still controversial and other toxins have been proposed (Duncan et al. 1992). A similar investigation into the causes of another motoneuron disease, lathyrism, showed that it might result from the ingestion of -N-oxalylam-ino-L-alanine (BOAA) found in the seeds of Lathyrus sativus (chickling or grass pea). The excitotoxic action of BOAA is antagonized in animal models by non-NMDA excitatory amino acid antagonists, BMAA by specific NMDA antagonists (Spencer et al. 1987b). Some forms of shellfish poisoning are characterized not by paralysis but by central nervous system symptoms including convulsions. An agent possibly responsible for these symptoms might be domoic acid found in seaweed (Chondria armata) and used as food by some edible mussels as proposed by Glavin and collaborators (1989). Preliminary animal data shows that broad spectrum excitatory amino acid antagonists such as kynurenic acid could be effective as antidotes for domoic acid poisoning (Glavin et al. 1990). In the above cases it would suffice to eliminate these plants from the diet to achieve prevention. However, these examples demonstrate that environmental agents exogenous to the human body might cause neuronal degeneration mediated by excitatory amino acid receptors. It would therefore be important to test excitatory amino acid antagonists in neurodegenerative diseases of as yet unknown origin, such as amyotrophic lateral sclerosis which occurrs in regions where Cycas is not part of the diet. They could prevent further neurological deterioration after the beginning of treatment. Indirect excitotoxicity following viral infection The aquired immunodeficiency syndrome (AIDS) is often accompanied by neurological symptoms including dementia. Histological observations led some authors to suggest that endogenous excitatory amino acids might be caused by the virus to reach excitotoxic levels. There are two lines of evidence supporting this hypothesis: i) quinolinic acid levels (see above) are elevated in the spinal cord fluid of HIV-1 infected patients (Heyes et al. 1991) and ii) mononuclear phagocytes infected with HIV-1 secrete a neurotoxin whose effect can be blocked by NMDA antagonists (Giulian et al. 1990). In some cases the measles virus also causes neuro-degeneration which resembles excitotoxic lesions. Andersson and his colleagues (1991) therefore applied the non-competitive NMDA-antagonist MK 801 to mice treated with a neurotropic measles virus and achieved neuroprotection compared to untreated animals. Neuronal protection in the ageing brain. Neurogenerative diseases of the ageing brain such as Alzheimer's and Parkinson's diseases, as mentioned above, are characterized by selective premature neuronal loss, but with the exception of the cases described above, no causative agents of an environmental nature such as poisons or viruses have yet been identified. Some investigators have therefore explored the possibility that endogenous or exogenous neurotoxins acting via excitatory amino acid receptors might be involved (Maragos et al. 1987). There is circumstantial evidence for such an involvement in Alzheimer's disease, as these authors have found a prominent loss of NMDA binding sites in the cortex and hippocampus of post-mortem brains (Greenamyre 1986), at least in patients who died in an advanced state of disease. In the same regions muscarinic cholinergic, benzodiazepine and GABA binding sites were not decreased relative to controls. Furthermore, -amyloid was seen to increase vulnerability of cortical neurons to excitotoxins (Koh et al. 1990). These results are consistent with the excitotoxic hypothesis as it could be imagined that precisely those neurons are affected that have a high density of NMDA receptors. A further observation possibly relevant to this hypothesis is that D-aspartate seems to accumulate in the brain with increasing age (Man 1983), however, the site of accumulation is white matter not gray. The excitotoxic hypothesis is only one of many advanced with respect to the causes of Alzheimer's disease, but it has the advantage that it will be testable as soon as NMDA antagonists are clinically available (Palmer and Gershon 1990). However, here again, one can only hope for cessation of the progressing deterioration after beginning treatment. c)Psychiatric disturbances This area is as speculative as the above mentioned ones. Attention has focussed on schizophrenia and anxiety, mainly based on theoretical considerations. This is due, at least for schizophrenia, to the fact that there are no 'schizophrenic' animals that can be used as models and that the current drugs are developed according to the dopamine hypothesis of schizophrenia for which there are many animal models, though none well-suited for testing the excitatory amino acid hypothesis. Schizophrenia. Freed (1988) has put forward a number of arguments for the involvement of excitatory amino acids in schizophrenia which center around the cortico-striatal pathway. He proposes that the antipsychotic effect of dopamine antagonists is due to a secondarily induced subsensitivity of the cortico-striatal excitatory amino acid synapse. His arguments are that anti-dopaminergic agents produce an acute non-specific sedation but that the antipsychotic effects develop more slowly over days and weeks, at a time when tolerance has developed to the sedative effects. Dopaminergic supersensitivity, also known to develop only after repeated administration of strong dopamine receptor antagonists, might be responsible for the tolerance to sedation. Because the corticostriatal excitatory synapse is located on the same dendritic spines of medium spiny neurons as nigro-striatal dopaminergic synapses, the former synapse may become secondarily subsensitive. In support of this hypothesis are the observations that dopamine inhibits cortically evoked excitatory postsynaptic potentials (EPSPs) in striatal cells (Herrling and Hull 1980) and repeated neuroleptic administration to mice reduces their sensitivity to quisqualate (Freed 1988). Non-NMDA receptors might be the receptors predominantly involved in the cortico-striatal EPSP (Herrling et al. 1983, Herrling 1985), however, NMDA-receptors may also play a role in this synapse (Cherubini et al. 1988). It will be of interest to learn wheather non-NMDA antagonists such as CNQX (Honore 1989) cause a haloperidol-like catalepsy. If not, such agents might turn out to be antipsychotics with lower incidence of exrapyramidal side-effects in clinical use (Meldrum and Kerwin 1987). Further evidence linking excitatory amino acid receptors and schizophrenia are the finding that a glutamate receptor gene is expressed in lower quantity in schizophrenics respective to normals (Harrison 1991) and that NMDA receptor mediated glutamate release is deficient in synaptosomes from schizophrenics (Sherman et al. 1991). Anxiety. The idea that competitive NMDA antagonists might be anxiolytic in man comes from observations in animal tests indicating that they were active in conflict situations but were different in many respects from benzodiazepines (Liebman et al. 1988, Stephens et al. 1988, Bennett et al. 1990, Dunn et al. 1990, Kehne et al. 1991, Serrano et al. 1989, Trullas et al. 1989). Drugs of abuse Several lines of evidence indicate an interaction of NMDA receptors with tolerance phenomena: i) NMDA antagonists inhibit tolerance to ethanol (Khanna et al. 1991) and ethanol withdrawal-induced seizures (Liljequist 1991). ii) There are differences in NMDA receptor densities in mice prone or resistant to ethanol withdrawal seizures (Valverius et al. 1990). iii) Trujillo and Akil (1991) report that MK 801 inhibits morphine tolerance and dependence in mice. d) Hormonal disturbances Several groups have described effects of excitatory amino acid modulating drugs on hormonal parameters (Van den Pol et al. 1990). N-Methyl-D-aspartate increased serum levels of luteinising hormone (LH) and growth hormone (GH) while kainic acid increased only GH levels (Brann and Mahesh 1991, Estienne et al. 1990a, 1990b, Farah et al. 1991, Lopez et al. 1990, Mason 1983, Urbanski and Ojeda 1990). Kynurenic acid, a broad spectrum excitatory amino acid antagonist, reduces synaptic excitation in slices of the supraoptic nucleus of rats, a nucleus known to regulate endocrine functions (Gribkoff K. and Dudek 1988). The competitive NMDA antagonist, 2-amino-5-phosphonopentanoate (AP5), suppresses pulsatile LH release in rats (Arslan et al. 1988). These observations open the possibility that excitatory amino acid modulating drugs might be of use in some forms of endocrine disturbances. e) Other neurological indications Muscle relaxation. NMDA antagonists have been shown to block synaptic responses involved in spinal reflexes (Davies 1988) and to be strong muscle relaxants in animal models of spasticity (Turski et al. 1987, 1988). It is therefore possible that they could be used in some forms of clinical spasticity. Disturbances of the auditory system. Broad spectrum antagonists of excitatory amino acids such as kynurenic acid (Bobbin and Caesar 1987) and a-D-glutamylamino-methylsulphonic acid (GAMS) affect the excitability of the auditory nerve after perfusion into the cochlea indicating that the hair cell transmitter might act at non-NMDA excitatory amino acid receptors (Ehrenberger 1983). In one clinical study (Ehrenberger 1983) both glutamate and glutamate diethylester were described to alleviate tinnitus (ear ringing) after i.v. injection. Anesthesia and analgesia. Many dissociative anesthetics have been found to be NMDA channel blockers (see Chapter 3 and ref. Lodge et al. 1988). The clinical use of these drugs, however, has been limited by psychotomimetic effects. The possibility must be explored that competitive NMDA antagonists at high doses might be anesthetics devoid of psychotomimetic properties (see below for discussion of side effects). Some animal data suggest that NMDA receptors are involved in nociceptive pathways (Aanonsen 1990, Davies and Lodge 1987, Eaton and Salt 1987, Haley et al. 1990, Klepstad et al. 1990, Salt 1992). Migraine. Some researchers have proposed that cortical spreading depression is the trigger for migraine attacks (Lauritzen 1990) and there is evidence linking NMDA receptors to this phenomenon (Marranes et al. 1988) leading to the suggestion that NMDA antagonists might be useful in treating migraine attacks (Hansen et al. 1988). Recently it was reported that excitatory amoino acid levels are elevated in migraine (Ferrari et al. 1990). Cognition enhancers. NMDA antagonists have been shown to impair some forms of memory formation (see below). This has led to the hypothesis that a moderate up-regulation of NMDA receptor function could lead to an improved cognitive function without excitotoxic or pro-convulsive effects. A site of choice for such an up-regulation is the strychnine- insensitive modulatory glycine site (SIGS) on the NMDA receptor (Johnson and Ascher 1987, Thomson 1990). A D-serine analogue (D-cycloserine) has been found to have partial agonistic properties at the SIGS (Henderson et al. 1990, Emmett et al 1991, Hood et al. 1989), and indeed displays cognitive enhancing properties in animals (Herberg and Rose 1990, Monahan et al 1989, Thompson et al. 1992). C) SIDE EFFECTS It can be predicted that peripheral side effects of excitatory amino acid modulating drugs resulting from interactions with peripheral excitable tissue will be relatively few since in contrast to other transmitter systems such as the acetylcholine, noradrenaline, dopamine and serotonin systems, excitatory amino acid receptors seem with very few exceptions (Bertrand et al. 1992, Erdoe 1991, Moroni 1986, Wiley 1991) to be confined to the central nervous system. Nevertheless, as with most other therapeutically effective chemical agents it is to be expected that the clinical use of drugs modulating excitatory amino acid systems will be limited by side effects. The nature of limiting side effects will probably be depend on the potential therapeutic indication. In the following, some side effects that can be inferred from the neurobiology of excitatory amino acids are discussed. Toxicological organ-specific side effects which are independent of the interaction with excitatory amino acid receptors are not discussed as they might vary with the chemical nature of the agents used. a) Muscle relaxation and sedation These properties of excitatory amino antagonists (see above) might be a limiting factor in their use in epilepsy. The therapeutic margin needs to be distinctly better than that of existing antiepileptic drugs to allow widespread use of excitatory amino acid antagonists in this indication. b) Psychotomimetic effects As mentioned above some NMDA channel blockers used as anesthetics in man, such as ketamine, display psychotomimetic effects. There is growing evidence that these effects are associated with the inhibition of the NMDA system and not to properties of dissociative anesthetics unrelated to excitatory amino acid systems (Lodge et al. 1988, ye et al. 1992). Nevertheless there are also data of France and coworkers (1989) that the competitive NMDA antagonist cis-(4-(phosphono-methyl)-2-piperidine carboxylic acid (CGS 19755) does not produce ketamine-like discriminative stimuli in Rhesus monkeys. Should psychotomimetic effects be associated with NMDA receptor blockade this would mean that such agents might have to be restricted to acute indications where such side-effects are not too disturbing in view of the clinical benefit, e.g. in head trauma. Furthermore the psychotomimetic effects might be dose-dependent and can possibly be dissociated from the beneficial effect of NMDA antagonists. c) Effects on learning performance and neuronal plasticity NMDA antagonists inhibit some forms of learning performance in rats (See chapter 10 and Morris et al. 1986, Parada-Turska and Turski 1990). If this also applies to human learning performance it would limit the use of such agents, e.g. in epilepsy where the onset of treatment is often before adult age. However, here again extrapolation to the clinical situation is difficult as it seems that the effect of NMDA antagonists is task-dependent and associated with high doses (Mondadori 1988). At lower doses performance in some paradigms of learning such as step-down shock avoidance are even improved by NMDA antagonists (Mondadori et al. 1988). This aspect requires special attention in the clinic. Neuronal plasticity during development has also been shown to be influenced by modulators of the NMDA receptor system (See chapter 11 [?] and Kleinschmidt et al. 1987). As plasticity probably also occurs in the human adult NMDA antagonists might interfere with this function. d) Effects on sensory systems In addition to the effects on auditory and nociceptive systems described above, there is considerable evidence that excitatory amino acid receptors are involved in all levels of sensory transmission, e.g., in the visual (Kemp and Sillito 1983, Miller et al. 186, Tang et al. 1988) and somatosensory systems (Mansbach 1991, Salt 1987, Salt and Eaton 1990). These processes involve both NMDA and non-NMDA receptors, but it is still unclear what contributions these different receptor systems make to sensory perception. There is evidence, however, that NMDA antagonists affect brightness discrimination in rats (Tang et al. 1988). It will be important to determine if effects of amino acid receptor modulating drugs on sensory processes in man are of such magnitude as to limit their clinical use. D) CONCLUSION Research into the neurobiology of excitatory amino acid systems has yielded a wealth of information on many physiological functions of the mammalian central nervous system. This was mainly due to the discovery of specific pharmacological tools in which J.C. Watkins played a predominant role ever since the discovery of excitatory amino acids. One consequence of this new knowledge was the proposal of many potential therapeutic indications for drugs interacting with these systems. If which modulates excitatory amino acids proves to be useful in any of these therapeutic areas then the neurobiological investigaton of excitatory amino acids will not only have been scientifically fascinating but will also have contributed to improved clinical treatment of patients, thereby reaching the ultimate goal of the biomedical researcher. ACKNOWLEDGEMENTS Thanks to Dr. Th. Bucher for commenting on the manuscript and Ms. H. Peis for secretarial assistance. E) REFERENCES see ALSD18B for references to this article == end of als 18A ==