NADPH oxidases (NOX), catalyzing the reduction of molecular oxygen to form the superoxide radical anion (•O₂⁻) and hydrogen peroxide (H₂O₂), are involved in several pathological conditions, such as ...stroke, diabetes, atherosclerosis, but also in chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, or multiple sclerosis. GKT136901 is a novel NOX-1/4 inhibitor with potential application in the areas of diabetic nephropathy, stroke, or neurodegeneration. In the present study, we investigated additional pharmacological activities of the compound with respect to direct free radical scavenging. GKT136901 did not interact with nitric oxide (•NO), •O₂⁻, or hydroxyl radicals (•OH), but it acted as selective scavenger of peroxynitrite (PON) already in the submicromolar concentration range. Alpha synuclein (ASYN) is a protein involved in the pathogenesis of Parkinson's disease and a known target for PON-dependent tyrosine nitration. Submicromolar concentrations of GKT136901 prevented tyrosine nitration and di-tyrosine-dependent dimer formation of ASYN by PON as indicated by Western blot and mass spectrometric analysis. GKT136901 itself was degraded when exposed to PON. In a human neuronal cell model, GKT136901 prevented both the depletion of reduced intracellular glutathione, and the degeneration of neurites when present during PON treatment of the cells. When GKT136901 was applied after PON treatment, no protective effect was observed, thus excluding an impact of GKT136901 on cellular death/survival pathways. In summary, selective scavenging of PON is an additional pharmacological property of the NOX-1/4 inhibitor GKT136901, and this may add to the efficiency of the drug in several disease models.
Animal models are a very important approach to study the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, ...characteristic functional changes have to be mimicked by neurotoxic agents. For instance, the application of the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is able to produce striking similarities to Parkinson's disease (PD) diagnosed in humans. MPTP is thought to selectively damage dopaminergic neurons predominantly those originating in the substantia nigra pars compacta (SNc) which leads to impaired dopaminergic neurotransmission accompanied by a loss of dopaminergic nerve terminals in the striatum. MPTP-induced neurochemical, behavioral, and histopathological alterations replicate very closely the clinical symptoms of PD patients, which will be discussed in this paper and render the MPTP model currently the most favored PD model to study therapeutic intervention strategies in an easy and reliable way in preclinical studies. We and many other research groups propose that the knowledge about the neurotoxic mechanisms of MPTP such as mitochondrial dysfunction with breakdown of energy metabolism and free radical production will help us to understand the underlying mechanisms of PD, which are not fully understood yet. In particular, the novel aspects of inflammatory processes and the involvement of reactive nitrogen species in addition to reactive oxygen species seem to be important milestones for a better understanding of the neurodegenerative effects of MPTP. In this review we focus on the MPTP mouse model which is easy practicable and widely used in neuroscience research and draw comparisons to the human pathology in PD.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The impact of pro‐inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α) in the pathology of Parkinson's disease (PD) and in MPTP neurotoxicity remains unclear. Here, male TNF‐α (–/–) ...deficient mice and C57bL/6 mice were treated with MPTP (4 × 15mg/kg, 24 h intervals) and in one series, thalidomide was administered to inhibit TNF‐α synthesis. Real‐time RT‐PCR revealed that the striatal mRNA levels of TNF‐α, of the astrocytic marker glial fibrillary acidic protein (GFAP) and of the marker for activated microglia, macrophage antigen complex‐1 (MAC‐1), were significantly enhanced after MPTP administration. Thalidomide (50 mg/kg, p.o.) partly protected against the MPTP‐induced dopamine (DA) depletion, and TNF‐α (–/–) mice showed a significant attenuation of striatal DA and DA metabolite loss as well as striatal tyrosine hydroxylase (TH) fiber density, but no difference in nigral TH and DA transporter immunoreactivity. TNF‐α deficient mice suffered a lower mortality (10%) compared to the high mortality (75%) seen in wild‐type mice after acute MPTP treatment (4 × 20mg/kg, 2 h interval). HPLC measurement of MPP+ levels revealed no differences in TNF‐α (–/–), wild‐type and thalidomide treated mice. This study demonstrates that TNF‐α is involved in MPTP toxicity and that inhibition of TNF‐α response may be a promising target for extending beyond symptomatic treatment and developing anti‐parkinsonian drugs for the treatment of the inflammatory processes in PD.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract l -DOPA-induced dyskinesia is known as involuntary debilitating movement, which limits quality of life in patients suffering from Parkinson's disease. The present study focuses on the role ...of the neurotransmitter noradrenaline (NA) on dyskinetic movements in comparison to the effect of l -DOPA. Rats were unilaterally lesioned with 6-hydroxydopamine and treated with l -DOPA/benserazide (6/15 mg/kg, p.o.) to induce stable dyskinetic movements. On the day of the experiment, NA (0.04 nmol/min, 0.4 nmol/min) and l -DOPA (0.04 nmol/min, 0.4 nmol/min) were perfused into the lesioned and non-lesioned striatum of dyskinetic rats using the reverse in vivo microdialysis technique. Neither NA nor l -DOPA treatment of the non-lesioned striatum produced any dyskinetic behavior. In contrast, administration of l -DOPA 0.4 nmol/min into the lesioned striatum led to a significant increase in dyskinesia indicated by abnormal axial, limb and orolingual movements. Notably, perfusion with NA 0.4 nmol/min into the lesioned striatum revealed a highly significant induction of dyskinetic movements, which are similar to the dyskinesia subtype profile of l -DOPA. In conclusion, NA is as potent as l -DOPA to express dyskinetic movements in l -DOPA-primed rats.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract Dyskinesia eventually develops in the majority of Parkinson's disease patients treated with l -3,4-dihydroxyphenylalanine ( l -DOPA). We have investigated the effect of an acute and local ...administration of l -DOPA, GABA and glutamate to provoke dyskinetic movements in three basal ganglia structures (striatum, globus pallidus (GP) and substantia nigra pars reticulata (SNr)) of chronically l -DOPA-treated, unilaterally 6-hydroxydopamine-lesioned rats. We demonstrated that l -DOPA administration into the lesioned striatum using the technique of reverse in vivo microdialysis was an effective trigger to switch on dyskinesia. Notably, local l -DOPA perfusion at the same concentration in the ipsilateral GP and SNr did not provoke significant dyskinetic behaviour. Neither GABA nor glutamate triggered dyskinetic movements in the striatum, GP or SNr. We postulate a site-specific action of l -DOPA for the evocation of already established dyskinesia since l -DOPA in the striatum but not in the GP or SNr switched on dyskinetic behaviour.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Many behavioral functions—including sensorimotor, attentional, memory, and emotional processes—have been associated with hippocampal processes and with dopamine transmission in the medial prefrontal ...cortex (mPFC). This suggests a functional interaction between hippocampus and prefrontal dopamine. The anatomical substrate for such an interaction is the intimate interconnection between the ventral hippocampus and the dopamine innervation of the mPFC.
The present study yielded direct neurochemical evidence for an interaction between ventral hippocampus and prefrontal dopamine transmission in rats by demonstrating that subconvulsive stimulation of the ventral hippocampus with
N-methyl-
d-aspartate (NMDA; 0.5 μg/side) activates dopamine transmission in the mPFC. Postmortem measurements revealed that bilateral NMDA stimulation of the ventral hippocampus, resulting in locomotor hyperactivity, increased the homovanillic acid/dopamine ratio, an index of dopamine transmission, in the mPFC; indices of dopamine transmission in any of five additionally examined forebrain regions (amygdala, nucleus accumbens shell/core, lateral prefrontal cortex, caudate putamen) were unaltered.
In vivo microdialysis measurements in freely moving rats corroborated the suggested activation of prefrontal dopamine transmission by demonstrating that unilateral NMDA stimulation of the ventral hippocampus increased extracellular dopamine in the ipsilateral mPFC.
The suggested influence of the ventral hippocampus on prefrontal dopamine may be an important mechanism for hippocampo-prefrontal interactions in normal behavioral processes. Moreover, it indicates that aberrant hippocampal activity, as found in neuropsychiatric diseases, such as schizophrenia and mood disorders, may contribute to disruption of certain cognitive and emotional functions which are extremely sensitive to imbalanced prefrontal dopamine transmission.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Depression is one of the most common human illnesses and is of immense clinical and economic significance. Knowledge of the neuro-psychology, -biology and -pharmacology of depression is limited, as ...is the efficacy of antidepressant treatment. In terms of depression aetiology, whilst the evidence for causal mechanisms is sparse, some genomic and environmental factors associated with increased vulnerability have been identified. With regards to the latter, the environments in which human infants and children develop are fundamental to how they develop, and parental loss, emotional and physical neglect, and abuse have been shown to be associated with: traits of depression, traits of predisposition to depression triggered by subsequent life events, and associated physiological abnormalities, across the life span. Studies of postnatal environmental manipulations in rodents and primates can potentially yield evidence that abnormal early-life experience leading to dysfunction of the neurobiology, physiology and behaviour of emotion is a general mammalian characteristic, and therefore, that this approach can be used to develop animal models for depression research, with aetiological, face, construct and predictive validity. The establishment of models with such validity, if at all achievable, will require a sophisticated combination of (1) appropriate postnatal manipulations that induce acute stress responses in the infant brain which in turn lead to long-term neurobiological consequences, and (2) appropriate behavioural and physiological assays to identify and quantify any depression-like phenotypes resulting from these long-term neurobiological phenotypes. Here, we review some of the evidence—positive and negative—that neglect-like environments in rat pups and monkey infants lead to long-term, depression-like behavioural traits of reduced motivation for reward and impaired coping with adversity, and to altered activity in relevant physiological homeostatic systems.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PDF
