Francois P. Viljoen

Social isolation rearing induces mitochondrial, immunological, neurochemical and behavioural deficits in rats, and is reversed by clozapine or N–acetyl cysteine

Apart from altered dopamine (DA) function, schizophrenia displays mitochondrial and immune-inflammatory abnormalities, evidenced by oxidative stress, altered kynurenine metabolism and cytokine release. N-acetyl cysteine (NAC), an antioxidant and glutamate modulator, is effective in the adjunctive treatment of schizophrenia. Social isolation rearing (SIR) in rats is a valid neurodevelopmental animal model of schizophrenia. This study evaluated whether SIR-induced behavioural deficits may be explained by altered plasma pro- and anti-inflammatory cytokines, kynurenine metabolism, and cortico-striatal DA and mitochondrial function (via adenosine triphosphate (ATP) release), and if clozapine or NAC (alone and in combination) reverses these changes. SIR induced pronounced deficits in social interactive behaviours, object recognition memory, and prepulse inhibition (PPI), while simultaneously increasing striatal but reducing frontal cortical accumulation of ATP as well as DA. SIR increased pro- vs. anti-inflammatory cytokine balance and altered kynurenine metabolism with a decrease in neuroprotective ratio. Clozapine (5mg/kg/day×14days) as well as clozapine+NAC (5mg/kg/day and 150mg/kg/day×14days) reversed these changes, with NAC (150mg/kg/day) alone significantly but partially effective in some parameters. Clozapine+NAC was more effective than clozapine alone in reversing SIR-induced PPI, mitochondrial, immune and DA changes. In conclusion, SIR induces mitochondrial and immune-inflammatory changes that underlie cortico-striatal DA perturbations and subsequent behavioural deficits, and responds to treatment with clozapine or NAC, with an additive effect following combination treatment. The data provides insight into the mechanisms that might underlie the utility of NAC as an adjunctive treatment in schizophrenia.

Role of monoamine oxidase, nitric oxide synthase and regional brain monoamines in the antidepressant-like effects of methylene blue and selected structural analogues

Dual action antidepressants have important therapeutic implications. Methylene blue (MB), a charged compound structurally related to tricyclic antidepressants, acts on both monoamine oxidase (MAO) and the nitric oxide (NO)-cGMP pathway, and has demonstrated antidepressant activity in rodents. We investigated the antidepressant properties of MB and selected structural analogues and whether their actions involve MAO, NO synthase (NOS) and regional brain monoamines. Acute imipramine (IMI, 15 mg/kg), saline, MB, acriflavine (ACR), methylene green (MG), methylene violet (MV), thionine (THI) and tacrine (TAC) (1-60 mg/kg i.p.) were tested for antidepressant activity in the forced swim test (FST), as well as MAO-A/B inhibitory activity. Active antidepressant compounds were subsequently studied at their most effective dose during sub-chronic treatment, followed by behavioural sampling in the FST and assay of cortico-limbic monoamines and hippocampal nitrate (for NOS activity). Only IMI, MB (15, 30, 60 mg/kg) and MG (7.5, 25, 40 mg/kg) reduced immobility in the acute FST. MB, MG and ACR were potent inhibitors of especially MAO-A. Following sub-chronic treatment, IMI (15 mg/kg) increased noradrenergic behaviour in the FST, while MB (15 mg/kg) and MG (15 mg/kg) enhanced serotonergic behaviour. MB and MG bolstered cortico-limbic serotonin (5HT) levels and to a lesser extent l-norepinephrine (l-NE), but did not significantly alter regional dopamine (DA) levels. MB, and to lesser degree MG, reduced hippocampal nitrate levels. MB and MG present with structure-specific antidepressant-like effects following acute and sub-chronic treatment, possibly involving NOS and MAO-A inhibition and cortico-limbic 5HT and l-NE release. A role for MAO-B and DA appears minimal.

Corticolimbic changes in acetylcholine and cyclic guanosine monophosphate in the Flinders Sensitive Line rat: a genetic model of depression

Objective: Depression is suggested to involve disturbances in cholinergic as well as glutamatergic pathways, particularly the N-methyl-d-aspartate receptor-mediated release of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). The aim of this study was to determine whether the Flinders Sensitive Line (FSL) rat, a genetic model of depression, presents with corticolimbic changes in basal acetylcholine (ACh) levels and NO/cGMP signalling. Methods: Basal levels of nitrogen oxides (NOx) and both basal and l-arginine-stimulated nitric oxide synthase (NOS) formation of l-citrulline were analysed in hippocampus and frontal cortex in FSL and control Flinders resistant line (FRL) rats by fluorometric and electrochemical high-performance liquid chromatography, respectively. In addition, ACh and cGMP levels were analysed by liquid chromatography tandem mass spectrometry and radioimmunoassay, respectively. Results: Significantly elevated frontal cortical but reduced hippocampal ACh levels were observed in FSL versus FRL rats. Basal cGMP levels were significantly reduced in the frontal cortex, but not hippocampus, of FSL rats without changes in NOx and l-citrulline, suggesting that the reduction of cGMP follows through an NOS-independent mechanism. Conclusions: These data confirm a bidirectional change in ACh in the frontal cortex and hippocampus of the FSL rat, as well as provide evidence for a frontal cortical ACh-cGMP interaction in the depressive-like behaviour of the FSL rat.

The Design and Evaluation of an l-Dopa–Lazabemide Prodrug for the Treatment of Parkinson’s Disease

l-Dopa, the metabolic precursor of dopamine, is the treatment of choice for the symptomatic relief of the advanced stages of Parkinson’s disease. The oral bioavailability of l-dopa, however, is only about 10% to 30%, and less than 1% of the oral dose is estimated to reach the brain unchanged. l-Dopa’s physicochemical properties are responsible for its poor bioavailability, short half-life and the wide range of inter- and intrapatient variations of plasma levels. An l-dopa–lazabemide prodrug is proposed to overcome the problems associated with l-dopa absorption. Lazabemide is a monoamine oxidase (MAO)-B inhibitor, a class of compounds that slows the depletion of dopamine stores in Parkinson’s disease and elevates dopamine levels produced by exogenously administered l-dopa. l-Dopa was linked at the carboxylate with the primary aminyl functional group of lazabemide via an amide, a strategy which is anticipated to protect l-dopa against peripheral decarboxylation and possibly also enhance the membrane permeability of the prodrug. Selected physicochemical and biochemical properties of the prodrug were determined and included lipophilicity (logD), solubility, passive diffusion permeability, pKa, chemical and metabolic stability as well as cytotoxicity. Although oral and i.p. treatment of mice with the prodrug did not result in enhanced striatal dopamine levels, 3,4-dihydroxyphenylacetic acid (DOPAC) levels were significantly depressed compared to saline, l-dopa and carbidopa/l-dopa treatment. Based on the results, further preclinical evaluation of the l-dopa–lazabemide prodrug should be undertaken with the aim of discovering prodrugs that may be advanced to the clinical stages of development.

The law and purity in Matthew; Jesus touching a bleeding woman and a dead girl (Mt 9:18-26)

This article investigates the double story in Matthew of Jesus touching a woman with blood flow and a dead girl, with specific reference to purity regulations of the Hebrew Bible. According to Matthew it seems that Jesus did not perform any purity rituals after touching the impure woman and girl. Such negligence would have caused serious repercussions amongst the spectators. In the Sermon on the Mount Jesus explicitly states that He did not come to abolish the Law, but in this double story Jesus apparently abrogates purity regulations. It is suggested that Matthew purposefully describes these events to demonstrate how these Laws found their fulfilment in Jesus. Jesus is depicted as Emmanuel and Saviour. Instead of Him being polluted by touching these persons, Jesus cleanses the impure woman and raises the dead girl to life. As Holy One purity flowed from Him to the defiled persons, so that they could be cleansed without Him being polluted. These acts of Jesus form part of the coming of the Kingdom of heaven. By accepting Jesus as their saviour, the Matthean community shares the benefits of his purifying power. Their purity is no longer dependent on external purity regulations, but on the cleansing power of Jesus, the Holy One.

Angelic appearances in Matthew's infancy narratives

Angelic appearances function prominently in the birth narratives of Matthew. An angel of the Lord appears to Joseph (Mt. 1:20; 2:12, 13, 19 and 22). Besides these explicit references to the angel, the first Gospel also refers to the guidance by an “unusual” star (Mt. 2:1-2 and 9-10). The appearance of the angel of the Lord to Joseph is investigated within the context of such appearances in New Testament times. Furthermore, the appearance of the star is investigated in the light of the views of stars in that period of time. The goal is to establish the nature of these appearances and the relation between them.