Antidepressants reveal differential effect against 1-methyl-4-phenylpyridinium toxicity in differentiated PC12 cells.

Treatment of depression may ameliorate the cognitive disability and motor slowness in Parkinson's disease. It has been shown that antidepressants, including fluoxetine, may attenuate or exacerbate neuronal cell death. The present study assessed the effect of antidepressants (amitriptyline, tranylcypromine and fluoxetine) against the toxicity of 1-methyl-4-phenylpyridinium (MPP(+)) in relation to the mitochondria-mediated cell death process in differentiated PC12 cells. Amitriptyline and tranylcypromine attenuated the MPP(+)-induced cell death that may be associated with mitochondrial membrane permeability change and oxidative stress. Both compounds prevented the loss of the mitochondrial transmembrane potential, over-expression of Bax, reduction in Bcl-2 level, cytochrome c release, caspase-3 activation, formation of reactive oxygen species and depletion of GSH. The inhibitory effect of tranylcypromine was greater than that of amitriptyline on the basis of concentration. In contrast, fluoxetine revealed a toxic effect and exhibited an additive effect against the toxicity of MPP(+). Results show that amitriptyline and tranylcypromine may attenuate the MPP(+) toxicity by suppressing the mitochondrial membrane permeability change that leads to cytochrome c release and subsequent caspase-3 activation. The effects seem to be associated with the inhibitory action on the formation of reactive oxygen species and the depletion of GSH. In contrast, fluoxetine seems to exert an additive toxic effect against neuronal cell damage by increasing mitochondrial damage and oxidative stress.

Mild encephalopathy with reversible lesion in the splenium of the corpus callosum and bilateral frontal white matter.

A 59-year-old man visited an emergency room due to the sudden onset of severe dysarthria with a drowsy mental status. MRI demonstrated T2 prolongation and restricted diffusion involving the splenium of the corpus callosum and bilateral frontal white matter neurological signs and symptoms were mild, and the recovery was complete within a week. Follow-up MRI performed one month later revealed complete resolution of the lesions. The clinical and radiological courses were consistent with previously reported reversible isolated splenial lesions in mild encephalitis/encephalopathy except for the presence of frontal lesions. This case suggests that such reversible lesions can occur outside the splenium.

Differential involvement of intracellular Ca2+ in 1-methyl-4-phenylpyridinium- or 6-hydroxydopamine-induced cell viability loss in PC12 cells.

1-Methyl-4-phenylpyridinium (MPP(+)) or 6-hydroxydopamine (6-OHDA) caused a nuclear damage, the mitochondrial membrane permeability changes, leading to the cytochrome c release and caspase-3 activation, the formation of reactive oxygen species and the depletion of GSH in PC12 cells. Nicardipine (a calcium channel blocker), EGTA (an extracellular calcium chelator), BAPTA-AM (a cell permeable calcium chelator) and calmodulin antagonists (W-7 and calmidazolium) attenuated the MPP(+)-induced mitochondrial damage and cell death. In contrast, the compounds did not reduce the toxicity of 6-OHDA. Treatment with MPP(+ )or 6-OHDA evoked the elevation of intracellular Ca(2+) levels. Unlike cell injury, addition of nicardipine, BAPTA-AM and calmodulin antagonists prevented the elevation of intracellular Ca(2+) levels due to both toxins. The results show that the MPP(+)-induced formation of the mitochondrial permeability transition seems to be mediated by elevation of intracellular Ca(2+) levels and calmodulin action. In contrast, the 6-OHDA-induced cell death seems to be mediated by Ca(2+)-independent manner.

Isolated Weakness of Middle, Ring, and Little Fingers due to a Small Cortical Infarction in the Medial Precentral Gyrus.

SMALL CORTICAL STROKES CAN PRODUCE PREDOMINANT ISOLATED WEAKNESS IN A PARTICULAR GROUP OF FINGERS: radial or ulnar. The traditional views are of point-to-point representations of each finger to neurons located in the precentral gyrus of the motor cortex such that the neurons of the radial fingers are located laterally and those of the ulnar fingers are located medially. We present a case of isolated weakness of middle, ring, and little fingers due to a small cortical infarction in the medial precentral gyrus.

Differential effect of calmodulin antagonists on MG132-induced mitochondrial dysfunction and cell death in PC12 cells.

Defects in proteasome function have been suggested to be involved in the pathogenesis of neurodegenerative diseases. We examined the effect of calmodulin antagonists on proteasome inhibitor-induced mitochondrial dysfunction and cell viability loss in undifferentiated PC12 cells. Caspase inhibitors (z-IETD.fmk, z-LEHD.fmk and z-DQMD.fmk) and antioxidants attenuated cell death and decrease in GSH contents in PC12 cells treated with 20 microM MG132, a proteasome inhibitor. Calmodulin antagonists (trifluoperazine, W-7 and calmidazolium) had a differential inhibitory effect on the MG132-induced cell death and GSH depletion depending on concentration with a maximal inhibitory effect at 0.5-1 microM. Addition of trifluoperazine and W-7 reduced the MG132-induced nuclear damage, loss of the mitochondrial transmembrane potential followed by cytochrome c release, formation of reactive oxygen species and elevation of intracellular Ca(2+) levels in PC12 cells. Calmodulin antagonists at 5 microM exhibited a cytotoxic effect on PC12 cells but attenuated the cytotoxicity of MG132. The results suggest that the toxicity of MG132 on PC12 cells is mediated by activation of caspase-8, -9 and -3. Trifluoperazine and W-7 at the concentrations of 0.5-1 microM may attenuate the MG132-induced viability loss in PC12 cells by suppressing change in the mitochondrial membrane permeability and by lowering of the intracellular Ca(2+) levels as well as calmodulin inhibition.

Comparison of the Protective Effect of Indole beta-carbolines and R-(-)-deprenyl Against Nitrogen Species-Induced Cell Death in Experimental Culture Model of Parkinson's Disease.

BACKGROUND: The membrane permeability transition of mitochondria has been suggested to be involved in toxic and oxidative forms of cell injury. Mitochondrial dysfunction is considered to play a critical role in neurodegeneration in Parkinson's disease. Despite the suggestion that indole beta-carbolines may be neurotoxic, these compounds provide a protective effect against cytotoxicity of other neurotoxins. In addition, the effect of indole beta-carbolines on change in the mitochondrial membrane permeability due to reactive nitrogen species (RNS), which may lead to cell death, has not been clarified. METHODS: Differentiated PC12 cells were used as the experimental culture model for the investigation of neuronal cell injury, which occurs in Parkinson's disease. The effect of indole beta-carbolines (harmalol and harmine) on differentiated PC12 cells against toxicity of S-nitroso-N-acetyl-DL-penicillamine (SNAP) was determined by measuring the effect on the change in transmembrane potential, cytochrome c release, formation of ROS, GSH contents, caspase-3 activity and cell viability, and was compared to that of R-(-)-deprenyl. RESULTS: Specific inhibitors of caspases (z-LEHD.fmk, z-DQMD.fmk) and antioxidants (N-acetylcysteine, dithiothreitol, melatonin, carboxy-PTIO and uric acid) depressed cell death in PC12 cells due to SNAP. beta-Carbolines and R-(-)-deprenyl attenuated the SNAP-induced cell death and GSH depletion concentration dependently with a maximal inhibitory effect at 25-50 microM. The compounds inhibited the nuclear damage, decrease in mitochondrial transmembrane potential, cytochrome c release and formation of reactive oxygen species caused by SNAP in PC12 cells. beta-Carbolines and R-(-)-deprenyl attenuated the H(2)O(2)-induced cell death and depletion of GSH. CONCLUSIONS: The results suggest that indole beta-carbolines attenuate the SNAP-induced viability loss in PC12 cells by inhibition of change in the mitochondrial membrane permeability, which may be caused by free radicals. Indole beta-carbolines appear to exert a protective effect against the nitrogen species-mediated neuronal cell injury in Parkinson's disease comparable to R-(-)-deprenyl.