1. The effect of N-acetyl-L-aspartic acid dilithium salt on dopamine release and synthesis in the rat striatum in vivo
V I Petrov, V S Sergeyev, N V Onishchenko Eur J Pharmacol. 2001 Mar 23;416(1-2):69-73. doi: 10.1016/s0014-2999(01)00872-x.
The effect of the dilithium salt of N-acetyl-L-aspartic acid on release and synthesis of dopamine in the striatum was investigated using microdialysis in freely moving rats. Intrastriatal infusion of 1 mM N-methyl-D-aspartate, an NMDA receptor agonist, augmented extracellular dopamine to 215% of baseline, while 1 mM dilithium N-acetyl-L-aspartate increased dopamine release to 190% of baseline in rat striatum. Infusion of DL-2-amino-5-phosphonopentanoic acid, a competitive NMDA receptor antagonist, prior to infusion of dilithium N-acetyl-L-aspartate did not significantly alter basal levels of dopamine, but reversed the dilithium N-acetyl-L-aspartate-evoked elevation in extracellular dopamine. Intrastriatal perfusion with 6-cyano-7-nitroquinoxaline-2,3-dione, an AMPA/kainate receptors antagonist, altered neither basal levels of dopamine nor dilithium N-acetylaspartate-induced dopamine release. When the striatum was continuously perfused with the inhibitor of L-aromatic amino acid decarboxylase, 3-hydroxybenzylhydrazine dihydrochloride (100 microM), both dilithium N-acetylaspartate and NMDA added to the perfusate increased extracellular 3,4-dihydroxyphenyl-L-alanine, reflecting the effect of the compounds on the biosynthesis of dopamine. The data suggest that availability of dilithium N-acetyl-L-aspartate to activate dopamine turnover and release in the rat striatum may be mediated by presynaptic NMDA heteroreceptors located at dopaminergic neurons.
2. In vitro and in vivo comparison of sulfur donors as antidotes to acute cyanide intoxication
S I Baskin, D W Porter, G A Rockwood, J A Romano Jr, H C Patel, R C Kiser, C M Cook, A L Ternay Jr J Appl Toxicol. 1999 May-Jun;19(3):173-83. doi: 10.1002/(sici)1099-1263(199905/06)19:33.0.co;2-2.
Antidotes for cyanide (CN) intoxication include the use of sulfane sulfur donors (SSDs), such as thiosulfate, which increase the conversion of CN to thiocyanate by the enzyme rhodanese. To develop pretreatments that might be useful against CN, SSDs with greater lipophilicity than thiosulfate were synthesized and assessed. The ability of SSDs to protect mice against 2LD50 of sodium cyanide (NaCN) administered either 15 or 60 min following administration of an SSD was assessed. To study the mechanism of action of the SSD, the candidate compounds were examined in vitro for their effect on rhodanese and 3-mercaptopyruvate sulfurtransferase (MST) activity under increasing SSD concentrations. Tests were conducted on nine candidate SSDs: ICD1021 (3-hydroxypyridin-2-yl N-[(N-methyl-3-aminopropyl)]-2-aminoethyl disulfide dihydrochloride), ICD1022, (3-hydroxypyridin-2-yl N-[(N-methyl-3-aminopropyl)]-2-aminoethyl disulfide trihydrochloride), ICD1584 (diethyl tetrasulfide), ICD1585 (diallyl tetrasulfide), ICD1587 (diisopropyl tetrasulfide); ICD1738 (N-(3-aminopropyl)-2-aminoethyl 2-oxopropyl disulfide dihydrochloride), ICD1816 (3,3'-tetrathiobis-N-acctyl-L-alanine), ICD2214 (2-aminoethyl 4-methoxyphenyl disulfide hydrochloride) and ICD2467 (bis(4-methoxyphenyl) disulfide). These tests demonstrated that altering the chemical substituent of the longer chain sulfide modified the ability of the candidate SSD to protect against CN toxicity. At least two of the SSDs at selected doses provided 100% protection against 2LD50 of NaCN, normally an LD99. All compounds were evaluated using locomotor activity as a measure of potential adverse behavioral effects. Positive hypoactivity relationships were found with several disulfides but none was found with ICD1584, a tetrasulfide. Separate studies suggest that the chemical reaction of potassium cyanide (KCN) and cystine forms the toxic metabolite 2-iminothiazolidine-4-carboxylic acid. An alternative detoxification pathway, one not primarily involving the sulfur transferases. may be important in pretreatment for CN intoxication. Although studies to elucidate the precise mechanisms are needed. it is clear that these newly synthesized compounds provide a new rationale for anti-CN drugs, with fewer side-effects than the methemoglobin formers.
3. Co-occurrence of the cyanotoxins BMAA, DABA and anatoxin-a in Nebraska reservoirs, fish, and aquatic plants
Maitham Ahmed Al-Sammak, Kyle D Hoagland, David Cassada, Daniel D Snow Toxins (Basel). 2014 Jan 28;6(2):488-508. doi: 10.3390/toxins6020488.
Several groups of microorganisms are capable of producing toxins in aquatic environments. Cyanobacteria are prevalent blue green algae in freshwater systems, and many species produce cyanotoxins which include a variety of chemical irritants, hepatotoxins and neurotoxins. Production and occurrence of potent neurotoxic cyanotoxins β-N-methylamino-L-alanine (BMAA), 2,4-diaminobutyric acid dihydrochloride (DABA), and anatoxin-a are especially critical with environmental implications to public and animal health. Biomagnification, though not well understood in aquatic systems, is potentially relevant to both human and animal health effects. Because little is known regarding their presence in fresh water, we investigated the occurrence and potential for bioaccumulation of cyanotoxins in several Nebraska reservoirs. Collection and analysis of 387 environmental and biological samples (water, fish, and aquatic plant) provided a snapshot of their occurrence. A sensitive detection method was developed using solid phase extraction (SPE) in combination with high pressure liquid chromatography-fluorescence detection (HPLC/FD) with confirmation by liquid chromatography-tandem mass spectrometry (LC/MS/MS). HPLC/FD detection limits ranged from 5 to 7 µg/L and LC/MS/MS detection limits were <0.5 µg/L, while detection limits for biological samples were in the range of 0.8-3.2 ng/g depending on the matrix. Based on these methods, measurable levels of these neurotoxic compounds were detected in approximately 25% of the samples, with detections of BMAA in about 18.1%, DABA in 17.1%, and anatoxin-a in 11.9%.
