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Abstract Antagonists at neurokinin 1 (NK1) receptors are attracting attention as potential treatments for depressive states in light of their actions in behavioural models predictive of antidepressant properties, their modulation [...]

L-dopa remains the most common treatment for Parkinson's disease. However, there is considerable interest in D3/D2 receptor agonists such as the novel agent S32504, since they exert antiparkinsonian properties in the absence of dyskinesia. An important question concerns the roles of D2 vs. D3 receptors, an issue we addressed with the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned nonhuman primate model of Parkinson's disease. In L-dopa-primed animals, S32504 (0.16-2.5 mg/kg p.o.) dose-dependently enhanced locomotor activity. This action was abolished by the D2 antagonist, L741,626 (2.5 mg/kg), but potentiated by the D3 antagonist, S33084 (0.63 mg/kg). Both antagonists were inactive alone. In drug-naive animals, a maximally effective dose of S32504 (2.5 mg/kg p.o.) displayed pronounced antiparkinsonian properties from the third day of administration, and its actions were expressed rapidly and durably. Thus, on day 33, antiparkinsonian properties of S32504 were apparent within 5 minutes and present for > 4 hours. Moreover, they were associated with neither wearing off nor significant dyskinesia. In conclusion, the novel D3/D2 agonist S32504 may offer advantages over L-dopa in the treatment of newly diagnosed parkinsonian patients. Its actions are expressed primarily by activation of D2, not D3, receptors. © 2006 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The complete amino acid sequence of neurotoxin I of the North African scorpion Androctonus australis Hector collected in Algeria (area of Chellala) is described. S-Methylation of cysteine residues formed by reduction of disulphide bonds was found useful for their identification in sequence determination using the phenylisothiocyanate method. From the N-terminal sequence (38 residues) established in the protein sequenator, and from the sequence of chymotryptic peptides the complete sequence of the protein has been deduced. The molecule consists of a single polypeptide chain cross-linked by four disulphide bridges. An isoneurotoxin (I') has been found in the venom of A. australis collected in Tunisia (area of Tozeur). It differs from neurotoxin I in the replacement, of the valine residue in position 17 by an isoleucine residue. [ABSTRACT FROM AUTHOR]

The complete amino acid sequence of neurotoxin II of the North African scorpion Androctonus auatratis Hector has been determined. From the N-terminal sequence (43 residues) obtained by automatic phenylisothiocyanate degradation in the protein sequenator, and from the sequence of tryptic peptides obtained by digestion of the reduced and methylated toxin of which amino groups had been previously masked by reaction with ethylthioltrifluoroacetate the complete amino acid sequence of the protein has been inferred. It is composed of a single polypeptide chain of 64 amino acid residues, including 8 half-cystines, ended by an histidinamide residue at the C-terminus. [ABSTRACT FROM AUTHOR]

Using the same method of purification of small molecular weight proteins worked out to obtain pure scorpion neurotoxins, four neurotoxins have been isolated from the venom of the cobra Naja haje. N. haje venom from the Miami Serpentarium contains two neurotoxins (I and II) whereas the venom of the same species obtained from the Institute Pasteur contains three neurotoxins (I, II' and III). Toxins I, II and II' consist of 61 amino acid residues and toxin III of 71. All are basic proteins containing four or five disulphide bridges. It is likely that the difference observed in neurotoxin composition of N. haje venoms from two different sources has a taxonomical counterpart, each venom originating from a different sub-species. [ABSTRACT FROM AUTHOR]

Recent data show that corticolimbic expression of the effector immediate early gene Arc is up-regulated by standard antidepressant drugs. Here, we tested the effect upon Arc expression of a novel antidepressant and selective 5-hydroxytryptamine/noradrenaline reuptake inhibitor (SNRI), (-)1-(1-dimethylaminomethyl) 5-methoxybenzocyclobutan-1-yl) cyclohexanol (S33005). Arc mRNA abundance in frontal, cingulate, orbital and parietal cortices, hippocampus (CA1 pyramidal layer) and striatum was elevated in rats treated daily for 14 but not 7 days with 10 mg/kg i.p. S33005 compared to saline. Fourteen but not 7 days treatment with 10 mg/kg i.p. venlafaxine, the prototypical SNRI, also elevated Arc mRNA, but its effects were not as pronounced and detected in fewer regions, compared to S33005. Neither S33005 nor venlafaxine altered Arc mRNA after acute injection nor altered brain derived neurotrophic factor mRNA after repeated administration. These data demonstrate that sustained treatment with SNRIs increases Arc expression in corticolimbic regions, and underpin previous neurochemical and behavioural evidence that S33005 is efficacious in models predictive of antidepressant action. [Copyright &y& Elsevier]