Still NAAG'ing After All These Years: The Continuing Pursuit of GCPII Inhibitors.

Nearly two decades ago, Joe Coyle published a single-authored review with the provocative title, The Nagging Question of the Function of N-Acetylaspartylglutamate (Coyle, 1997). In this review, Coyle documented NAAG's localization to subpopulations of glutamatergic, cholinergic, GABAergic, and noradrenergic neurons, Ca(2+)-dependent release, mGlu3 receptor agonist and NMDA receptor antagonist activity, and cleavage by the glial enzyme glutamate carboxypeptidase II (GCPII). However, at the time of his review, NAAG's physiological function as a neurotransmitter remained elusive. Ironically his review was published months following the discovery of the first potent and selective GCPII inhibitor, 2-(phosphonomethyl)pentanedioc acid (2-PMPA) (Jackson et al., 1996). Over the ensuing decades, over a dozen independent laboratories used 2-PMPA and other GCPII inhibitors to elucidate two distinct neurotransmitter functions for NAAG. Under basal conditions, when GCPII activity is relatively low, intact NAAG dampens synaptic activity via presynaptic mGlu3 receptor activation and NMDA receptor blockade. However, under stimulated conditions, NAAG release and GCPII activity are enhanced resulting in excess glutamate generation, activating NMDA and other glutamate receptors, often pathologically. Diverse classes of GCPII inhibitors have been synthesized and shown to increase NAAG, decrease glutamate, and provide robust efficacy in many disease models wherein abnormal glutamatergic transmission is presumed pathogenic. In addition, over the past 20 years, basic questions regarding NAAG's synthesis, packaging into vesicles, and receptor selectivity profile have been eloquently elucidated. The purpose of this chapter is to summarize these advances and the promise of regulating NAAG metabolism through GCPII inhibition as a therapeutic strategy.

Length-dependent axo-terminal degeneration at the neuromuscular synapses of type II muscle in SOD1 mice.

In motor neuron diseases, there is a prolonged period of time before any clinical symptoms begin to appear. During this time, distal axonal degeneration, or "dying back" axonopathy, begins to occur before the onset of clinical symptoms and motor neuron death. This preclinical degeneration is a hallmark of motor neuron diseases in both animal models and human patients. Generally, in muscles with mixed fiber types, distal degeneration occurs in fast-fatigable α-motor axons innervating type IIb muscle fibers before axons innervating slow, type I muscle fibers. We investigated whether the "dying back" axonopathy in a pure fast-fatigable α-motor axon nerve is a length-dependent process. The lateral thoracic nerve (LTN) exclusively consists of motor nerves that innervate the very thin cutaneous maximus muscle (CMM) that solely contains type II neuromuscular synapses. We characterized the LTN and CMM synapses both morphologically and physiologically in the superoxide dismutase 1 (SOD1) mutant mouse model of amyotrophic lateral sclerosis (ALS). By 60days of age, there was a significant "dying back" phenomenon at the caudal region while the rostral region remained intact. The longer axons innervating the caudal region appear to be more susceptible to degeneration in the SOD1 mouse indicating that the axonal degeneration of motor neurons innervating type II fibers is a length-dependent process. Additionally, we identified how the simplicity of the LTN-CMM system offers a better method to investigate axon degeneration in an ALS mouse model and may be used to investigate possible therapeutic compounds for axon protection and regeneration.

Generation of neurons by transient expression of neural bHLH proteins in mammalian cells.

Basic helix-loop-helix (bHLH) transcription factors are known to function during mammalian neurogenesis. Here we show that transient transfection of vectors expressing neuroD2, MASH1, ngn1 or related neural bHLH proteins, with their putative dimerization partner E12, can convert mouse P19 embryonal carcinoma cells into differentiated neurons. Transfected cells express numerous neuron-specific proteins, adopt a neuronal morphology and are electrically excitable. Thus, the expression of neural bHLH proteins is sufficient to confer a neuronal fate on uncommitted mammalian cells. Neuronal differentiation of transfected cells is preceded by elevated expression of the cyclin-dependent kinase inhibitor p27(Kip1) and cell cycle withdrawal. This demonstrates that the bHLH proteins can link neuronal differentiation to withdrawal from the cell cycle, possibly by activating the expression of p27(Kip1). The ability to generate mammalian neurons by transient expression of neural bHLH proteins should create new opportunities for studying neurogenesis and devising neural repair strategies.

International monitoring of adverse health effects associated with herbal medicines.

Herbal medicines are used in health care around the world and may increase in importance. There is much uncertainty, however, with regard to their composition, efficacy and safety. There is substantial evidence that herbal medicines can cause serious adverse reactions, but more data are needed as regard their nature, frequency and preventability. In this respect the Uppsala Monitoring Centre of the World Health Organization can play a crucial role. Better reporting of adverse reactions to herbal medicines is needed, in particular with regard to the precise identity and composition of these products. A consistent use by producers, regulators and reporters of the international Latin binomial nomenclature and the use of the new Herbal Anatomical Therapeutic Chemical (ATC) classification are recommended. Copyright (c) 2000 John Wiley & Sons, Ltd.

Inventory of plants used in traditional medicine in Somalia. IV. Plants of the families Passifloraceae-Zygophyllaceae.

Thirty-seven plants are listed, which are used by traditional healers in the central and southern parts of Somalia. For each species are listed: the botanical name with synonyms, collection number, vernacular name, medicinal use, preparation of remedy and dosage. Results of a literature survey are also reported including medicinal use, substances isolated and pharmacological effects. Three plants which should have been included in Part I of the series have been added and some corrections to that paper have been made. With these additions the series comprises 180 different plant species, distributed in 59 plant families.

Inventory of plants used in traditional medicine in Somalia. III. Plants of the families Lauraceae-Papilionaceae.

Thirty-five plants are listed, which are used by traditional healers in the central and southern parts of Somalia. For each species are listed: the botanical name with synonyms, collection number, vernacular name, medicinal use, preparation of remedy and dosage. Results of a literature survey are also reported including medicinal use, substances isolated and pharmacological effects.

Inventory of plants used in traditional medicine in Somalia. II. Plants of the families Combretaceae to Labiatae.

Fifty-nine plants are listed, which are used by traditional healers in the central and southern parts of Somalia. For each species are listed: the botanical name with synonyms, collection number, vernacular name, medicinal use, preparation of remedy and dosage. Results of a literature survey are also reported including medicinal use, substances isolated and pharmacological effects.

Microdontin A and B: Two New Aloin Derivatives from Aloe microdonta.

The leaf juice of ALOE MICRODONTA Chiov. is used in Somali traditional medicine as a remedy for jaundice and for topical treatment of skin diseases. Mucilage was precipitated from the fresh juice by addition of ethanol and the supernatant chromatographed on Amberlite XAD-2 to yield a fraction containing anthraquinone derivatives. Flash chromatography on silica gel followed by preparative TLC yielded aloin A and a new compound. Spectral data (mass, (1)H- and (13)C-NMR) identified this compound as a mixture of aloin A and B where the glucose of both compounds is esterified with 4-hydroxycinnamic acid at the 6'-position. The two compounds were denoted as microdontin A and B, respectively.

Pharmacologically active phenylpropanoids from Senra incana.

Coniferaldehyde, scopoletin, sinapaldehyde, and syringaldehyde were isolated from an aqueous extract of Senra incana. All four compounds inhibited prostaglandin synthetase in a dose-dependent way. Compared to aspirin, the potency of coniferaldehyde and scopoletin was about five times higher, whereas syringaldehyde and sinapaldehyde had about half the potency of this reference compound. On topical application, sinapaldehyde and scopoletin dose-dependently inhibited ethyl phenylpropiolate-induced edema of the rat ear. The active dose range was 1-10 micrograms/ear. Higher doses had a lower effect. Syringaldehyde was active in the range 20-100 micrograms/ear, whereas the effect of coniferaldehyde was inconclusive. Coniferaldehyde and sinapaldehyde inhibited electrically induced contractions of the guinea pig ileum in a dose-dependent way. Syringaldehyde showed a weak inhibition at a concentration of 550 microM.

Inventory of plants used in traditional medicine in Somalia. I. Plants of the families Acanthaceae-Chenopodiaceae.

Thirty-eight plants are listed, which are used by traditional healers in the central and southern parts of Somalia. For each species are listed: the botanical name with synonyms, collection number, vernacular name, medicinal use, preparation of remedy and dosage. Results of a literature survey are also reported including medicinal use, substances isolated and pharmacological effects.

Preliminary chemical characterization of pharmacologically active compounds in aqueous plant extracts.

A test system is described which, based on the use of ion exchangers, gel filtration on Sephadex, and extraction with organic solvents, gives information about the stability, molecular size, charge, and polarity of pharmacologically active compounds in aqueous plant extracts. Knowledge of these properties permits development of a suitable isolation method for the compounds. The method is illustrated by the identification of quaternary ammonium salts as responsible for the contracting activity on the isolated guinea pig ileum of an aqueous extract of roots of Maeura subcordata.