Extreme anticipation in young-onset Parkinson's disease.
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Adult↗
Biomedical subjects
I Ziv
Publications and source records attributed to I Ziv.
Role of apoptosis in the pathogenesis of Parkinson's disease: A novel therapeutic opportunity?
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Animals↗
Diagnosis of "non-organic" limb paresis by a novel objective motor assessment: the quantitative Hoover's test.
The differentiation of "non-organic" limb weakness from genuine paralysis is sometimes difficult in neurological practice. To address this problem, we developed a computerized quantitative method, based on the Hoover's test principle, that determines the extent of involuntary limb activation when contralateral movement is performed. Measurements of hip or arm extension isometric force are performed during direct maximal voluntary effort and during contralateral hip flexion. Maximal involuntary/voluntary force ratio (IVVR) is calculated. IVVR of the lower limbs in ten healthy subjects was 0.614, 0.044 (mean, SEM). Similar results were obtained from seven patients with genuine weakness and in the non-affected limbs of nine patients with "non-organic" mono- or hemiparesis. In contrast, IVVR in the affected limbs in the "non-organic" group was markedly increased (2.48, 0.61; P < 0.001). The same pattern was elicited in the upper limbs (2.27, 0.46 vs 0.406, 0.06; P < 0,001). We conclude that Hoover's sign in "nonorganic" paralysis is a preservation or increase of a normal synkinetic phenomenon. Quantitative measurement of the IVVR can serve as a useful ancillary test in diagnosing non-organic weakness in either lower or upper limbs.
Adult↗
Expression of cell cycle-related genes during neuronal apoptosis: is there a distinct pattern?
An emerging hypothesis considers the process of neuronal apoptosis as a consequence of unscheduled and unsynchronized induction of cell cycle mediators. Induction of several cell cycle genes precedes neuronal apoptosis and may be involved in determination of cell fate. We have now characterized changes in expression of cell cycle genes during apoptosis induced by oxidative stress in chick post-mitotic sympathetic neurons. Induction of cyclin B occurred prior to the commitment of neurons to both dopamine- and peroxide-triggered apoptosis. Both the neuronal death and the rise in cyclin B were inhibited by antioxidant treatment, suggesting a functional role for cyclin B induction during neuronal apoptosis. Induction of the cyclin dependent kinase CDK5 protein coincided with the time point when neurons were irreversibly committed to die. Expression of other cell cycle mediators such as cyclin D1 and the cyclin dependent kinases CDC2 and CDK2 was undetected and not induced by exposure to oxidative stress. Comparative analysis of the profile of cell cycle mediators induced during neuronal apoptosis of different neuronal cell populations revealed no distinct pattern of events. There are no cell cycle stage-specific mediators that are ultimately stimulated during neuronal apoptosis, suggesting that multiple pathways of re-activating the dormant cell-cycle, converge to determine entry into apoptosis. Nevertheless, the existence of some cell cycle mediators, that were not reported so far to be induced in post mitotic neurons during oxidative stress, substantiate them as part of the strong differentiating forces.
Animals↗
The effects of dietary-induced obesity on the biomechanical properties of femora in male rats.
OBJECTIVE: To assess the effects of diet-induced obesity (DIO), on the biomechanical and biochemical properties of the femur in mature male rats. DESIGN AND SUBJECTS: Two groups of male rats were studied. The DIO experimental group was fed a high caloric diet and a 31% sucrose solution as drinking fluid for a month, whereas the control group was fed lab chow and tap water. MEASUREMENT: Body weight; body water; lean body mass; femoral length; average cortical thickness; outer anteroposterior diameter; outer mediolateral diameter; cortex area; moment of inertia; cortical and cancellous bone hydration; tendon and muscle hydration; ash content of cortical and cancellous bone; ultimate load; deflection at ultimate load; ultimate strength; stiffness; elastic modulus and energy absorption capacity. RESULTS: 'Gainers' (final body weight in excess of three standard error of mean of the controls) were 19.1% heavier, with higher body fat, whereas body water, lean body mass, hydration of cancellous bone and ash content of cortical bone were lower, when compared to controls. Rats that failed to gain weight, despite the high caloric diet, were termed 'resisters' (weight gain less than three standard error of mean of the controls). Ultimate load, deflection at ultimate load and femoral energy absorption capacity were significantly higher in the experimental group when compared to the controls. However, no differences were found among the groups with respect to ultimate stress and stiffness. CONCLUSION: The weight gain produced by DIO may lead to bone adaptation and improved biomechanics.
Analysis of Variance↗
Enhanced oxidative stress and altered antioxidants in brains of Bcl-2-deficient mice.
Bcl-2 is an antiapoptotic protein located in the outer mitochondrial membrane. Cellular perturbations associated with programmed cell death may be the consequence of disrupted mitochondrial function as well as excessive production of reactive oxygen species (ROS). Numerous studies indicate that Bcl-2 is involved in opposing cell death induced by oxidative stimuli, but its mode of action is uncertain. We reexamined the role of Bcl-2 by using a loss-of-function model, Bcl-2 knockout mice. Brains from Bcl-2-deficient mice had a 43% higher content of oxidized proteins and 27% lower number of cells in the cerebellum relative to wild-type mice. Incubation of cerebellar neurons from Bcl-2 +/+ brains with 0.5 mM dopamine caused 25% cell death, whereas in Bcl-2-deficient cells, it resulted in 52% death; glial cells provided protection in both cultures. Splenocytes from Bcl-2-deficient mice were also killed more effectively by dopamine as well as paraquat. Bcl-2-deficient mice did not survive intraperitoneal injection of MPTP, which caused a decrease in dopamine level in the striatum of Bcl-2 +/- brains, which was more significant than in wild-type mice. When compared with Bcl-2 +/+ brains, brains of 8-day-old Bcl-2-deficient mice had higher activities of the antioxidant enzymes GSH reductase (192%) and GSH transferase (142%), whereas at the age of 30 days, GSH peroxidase was significantly lower (66%). Activities of GSH transferase and GSH reductase increased significantly (158 and 262%, respectively) from day 8 to day 30 in Bcl-2 +/+ mice, whereas GSH peroxidase decreased (31%) significantly in Bcl-2 -/- animals. In summary, our results demonstrated enhanced oxidative stress and susceptibility to oxidants as well as altered levels of antioxidant enzymes in brains of Bcl-2-deficient mice. It is concluded that Bcl-2 affects cellular levels of ROS, which may be due to an effect either on their production or on antioxidant pathways.
Animals↗
Enhanced fatigue during motor performance in patients with Parkinson's disease.
OBJECTIVE: To measure fatigue quantitatively during continuous motor performance in patients with PD. BACKGROUND: Enhanced fatigue on performance of motor tasks is a very frequent and disabling complaint of PD patients, and is poorly characterized and understood. Recent evidence suggests a role for mitochondrial dysfunction in the pathogenesis of PD. Reduced exercise capacity is one of the hallmarks of systemic mitochondrial impairment. METHODS: The authors used an automated system to measure muscle fatigue during a continuous (30-second), maximal, isometric forearm flexion in 17 PD patients and 10 age-matched control subjects. A fatigue index (FI) was then calculated. Peak force (PF) was measured as an internal standard of the examination. Measurements were performed before and 2 hours after an oral dose of levodopa/carbidopa (125 mg/12.5 mg). RESULTS: In PD patients there was a 50% increase in FI. The increased FI was often asymmetric and more pronounced on the side more affected by the disease. FI was significantly responsive to, and improved after, an oral dose of levodopa. The rate of improvement in FI induced by levodopa correlated with disease severity, as measured by the Unified Parkinson's Disease Rating Scale. No significant alterations in PF were observed. CONCLUSIONS: Enhanced muscle fatigue should be recognized as an integral part of the spectrum of motor impairment of PD. However, our data argue for its association with a central dopamine deficiency rather than with a muscle mitochondrial abnormality.
Adult↗
A cartilage matrix deficiency experimentally induced by vitamin B6 deficiency.
A vitamin B6-deficiency-induced disorder in avian articular cartilage resembling osteoarthritis has been further characterized. We measured several parameters of proteoglycan (PG) metabolism, i.e., fixed charge density and sulfated glycosaminoglycans (S-GAG) content in PN-deficient versus control articular cartilage and synovial fluid from the knee joint. Statistically significant changes were: 1) decreased content and increased extractability of total sulfated PGs from articular cartilage with guanidine HCl; 2) elevation of S-GAG concentration in synovial fluid; 3) increased plasma cystathionine (sulfur amino acid) levels. PG synthesis as assessed by 35SO4 incorporation into S-GAGs was not impaired. A lack of cartilage swelling in 0.15 M saline and the normal water content indicated that although disturbed, the collagen network was not disrupted. This finding was in agreement with a previous microscopic study that revealed no fissures in the articular cartilage. Previous findings of a normal aggregating PG size-distribution and absence of elevated metalloproteases made a disturbance of aggregating PG metabolism unlikely. Escape into the synovial fluid of small PGs, normally bound to articular collagen, was believed to result from an alteration in collagen molecular organization that could be secondary to elevated circulating SH-compounds.
Animals↗
Levodopa induces apoptosis in cultured neuronal cells--a possible accelerator of nigrostriatal degeneration in Parkinson's disease?
Apoptosis is an active, intrinsic cell suicide program. We recently suggested that it may have a role in the death of nigrostriatal dopaminergic neurons in Parkinson's disease (PD). We now report that levodopa, the current major therapy for PD, is a potent inducer of apoptosis in cultured postmitotic chick sympathetic neurons. Levodopa, in a concentration range of 0.01-0.3 mM, caused the characteristic apoptotic cascade of cell shrinkage, massive membrane blebbing, and nuclear fragmentation, as evident by nuclear flow cytometry and fluorescence microscopy. Levodopa-induced apoptosis was inhibited by antioxidants, indicating that it may be mediated by autooxidation-reactive species. Levodopa treatment for PD may therefore constitute an additional challenge for the defective apoptosis-inhibiting systems in the nigrostriatal neurons. Despite reassuring data from some, but not all, previous studies, these findings suggest that the possible in vivo toxic effects of levodopa on the survival of the remaining nigral neurons should be further explored.
Animals↗
Induction of mitosis-related genes during dopamine-triggered apoptosis in sympathetic neurons.
It was suggested that neuronal degeneration in Parkinson's Disease (PD) is linked to dopamine (DA) toxicity. Dopamine has been shown to induce programmed cell death in both neuronal and non-neuronal cell types. We examined the molecular changes associated with dopamine-triggered apoptosis in sympathetic neurons using the differential display approach, and isolated 14 different DA responsive genes whose expression is altered during the early stages of the apoptotic process. Nine of these genes are upregulated and five are downregulated in response to DA exposure. Two of the upregulated genes were identified as cyclin B2 and a chicken homologue of chaperonin, a member of the heat shock protein family. Total increase in mRNA expression of both genes after 12 hours of exposure to DA was 40%. These two genes participate in cell cycle control and are specifically involved in determining entry of dividing cells into mitosis. Upregulation of mitosis-related genes in postmitotic sympathetic neurons undergoing apoptosis, may be indicative of an abortive attempt of these neurons to re-enter the cell cycle prior to their death. Possible implications to neuronal degeneration in PD are discussed.
Animals↗
Modulation of control mechanisms of dopamine-induced apoptosis--a future approach to the treatment of Parkinson's disease?
The cause for the progressive and selective degeneration of the dopaminergic (DA) nigrostriatal neurons in Parkinson's disease (PD) is still unknown. We suggest a novel approach, that links this neuronal degenerative process to inappropriate triggering of apoptosis, an active, controlled program of cellular self destruction, by excess oxidative stress mediated by DA metabolism. In support of this concept, we found that DA, the endogenous neurotransmitter, is capable of initiating apoptosis in cultured, postmitotic chick sympathetic neurons, an observation further extended to other cellular systems (PC-12 cells, cerebellar granular cells, thymocytes, splenocytes). In comparing the relative apoptosis-triggering potency of other mononamine neurotransmitters, DA was found to be the most active, whereas norepinephrine and serotonin had a moderate and a mild effects, respectively. This grading can be correlated with the relative involvement of the relevant neuronal systems (i.e., substantia nigra, locus ceruleus and raphe nuclei) in PD. We therefore hypothesize that neuronal degeneration in PD may be caused, at least in part, by a failure, either inherited or acquired, in cellular control systems of apoptosis, that may normally restrain the lethal potential of these endogenous neuro-transmitters and their potentially-toxic oxidation products. We therefore point at apoptosis-control systems as a critical scene of events, where the fate of nigrostriatal neurons is ultimately determined, and whose modulation may yield attenuation of the neuronal degenerative process. In support of this concept, we found that vector-driven stable expression of the proto-oncogene bcl-2, an inhibitor of apoptosis, can exert powerful cellular protection against DA toxicity in rat pheochromocytoma PC-12 cells. Furthermore, cell extracts from bcl-2-expressing cells were found to markedly inhibit in vitro oxidation of DA and production of DA-melanin. We also found that expression of bcl-2 can inhibit the decrease in intracellular reduced thiol (-SH) groups which we observed following exposure to DA. Research of the bcl-2 system and associated control mechanisms of apoptosis, possibly acting in association with intra-cellular anti-oxidant pathways, may therefore lead to novel therapeutic approaches for neuroprotection in PD.
Animals↗
Nigrostriatal neuronal death in Parkinson's disease--a passive or an active genetically-controlled process?
The cause for the rather selective degeneration of the nigrostriatal dopaminergic (DA) neurons in Parkinson's disease (PD) is still enigmatic. The major current hypothesis suggests that nigral neuronal death in PD is due to excessive oxidant stress generated by auto- and enzymatic oxidation of DA, formation of neuromelanin and presence of high concentrations of iron. Such cell death is generally regarded as a passive, necrotic process, mainly resulting from membrane lipid peroxidation, leading to its dysfunction and rupture and then to neuronal disintegration. We suggest a novel approach, that views neuronal degeneration in PD as an active process that occurs mainly the nuclear level. Our concept is based on the following observations: (1) Nigral histopathology in PD is characterized by a slow, protracted degeneration of individual neurons. We propose that it may be due to apoptosis [programmed cell-death (PCD), an active, genetically-controlled, intrinsic program of cell "suicide"] rather than to necrotic cell death. (2) DA exerts antitumor effect on melanoma and neuroblastoma cells. (3) Many anticancer drugs, trigger PCD by causing DNA damage. (4) DA has been shown to be genotoxic. (5) We recently first showed that DA, the endogenous neurotransmitter in the nigra, can trigger apoptosis in cultured, postmitotic sympathetic neurons. (6) We have also shown that PC-12 cells, transfected with the bcl-2 gene (a proto-oncogene that inhibits PCD) are relatively resistant to DA-apoptotic effect. Degeneration of nigrostriatal neurons in PD may therefore be linked to dysregulation of the control mechanisms that normally restrain the PCD-triggering-potential of their own neurotransmitter.
Animals↗
Ultrasound velocity and broadband attenuation as predictors of load-bearing capacities of human calcanei.
The main purpose of this study was to determine whether calcaneal ultrasound parameters, measured in the mediolateral direction, reflect load-bearing capacities of human calcanei. Broadband ultrasound attenuation (BUA) and ultrasound velocity (UV) were measured in 20 cadaveric calcanei with a mean age of 74.1 (SD 8.8). Normalized BUA (nBUA) was determined by dividing BUA by the calcaneal thickness obtained using a pulse-echo technique. The bone mineral density (BMD) of each calcaneus was measured by quantitative computed tomography. The calcanei were embedded in PMMA to simulate the midstance physiologic orientation during compressive testing in the load-bearing direction. The failure load, stiffness, and energy absorption were determined for each calcaneus. It was shown that BMD was well correlated with all ultrasound parameters (P < 0.0001). BMD, BUA, nBUA, and UV were all significantly associated with calcaneal failure load, stiffness, and energy absorption capacity (P < 0.05). nBUA was found to be the strongest predictor of all compressive properties. BUA and BMD demonstrated similar predictability of stiffness and energy absorption capacity, however, BUA showed a more significant relationship to the failure load of the calcaneus than did BMD. UV was found to be inferior to BMD, as well as BUA or nBUA, in assessing failure load, stiffness, and energy absorption capacity. It was also shown that nBUA was superior to BUA in the assessment of load-bearing capacity, but not in the prediction of BMD. Multivariate regression analysis showed that the combination of BUA or nBUA with UV did not improve the predictability of failure load, stiffness, and energy absorption capacity over that of BUA or nBUA alone (P > 0.5).
Absorptiometry, Photon↗
Dopamine-melanin induces apoptosis in PC12 cells; possible implications for the etiology of Parkinson's disease.
The function of neuromelanin (NM), the oxidized dopamine (DA) polymer, within the DA-producing cells in the human and primate substantia nigra (SN), is still an enigma. Some studies show that the vulnerability of nigral neurons in Parkinson's disease is correlated to their toxic NM content, while others suggest that it contributes to cellular protection. We showed recently that DA, the endogenous nigral neurotransmitter, triggers apoptosis, an active program of cellular self-destruction, in neuronal cultures. In the present study, we exposed cells to synthetic dopamine-melanin (DA-M) and analysed the cellular and genetic changes. We found that exposure of PC12 cells to DA-M (0.5 mg/ml for 24 h) caused 50% cell death, as indicated by trypan blue exclusion assay and 3H-thymidine incorporation. Gel electrophoresis DNA analysis of PC12 cells treated with DA-M showed the typical apoptotic DNA ladder, indicating inter-nucleosomal DNA degradation. The DNA fragmentation also was visualized histochemically in situ by DNA end-labeling staining (the TUNEL method). The FeCl2 (0.05 mM) significantly increased DA-M toxicity, while desferrioxamine, an iron chelator, totally abolished the additive toxicity of iron. The contribution of oxidative stress in this model of DA-M-induced cell death was examined using various antioxidants. In contrast to DA, inhibition of DA-M toxicity antioxidants by reduced glutathione (GSH), N-acetyl cysteine, catalase and Zn/Cu superoxide dismutase (SOD) was very limited. In conclusion, we found that DA-M may induce typical apoptotic death in PC12 cells. Our findings support a possible role of NM in the vulnerability of the dopaminergic neural degeneration in Parkinson's disease. The differential protective effect by antioxidants against toxicity of DA and DA-M may have implications for future neuroprotective therapeutic approaches for this common neurological disorder.
Animals↗
The ability of quantitative ultrasound to predict the mechanical properties of trabecular bone under different strain rates.
The ability of quantitative ultrasound to predict the mechanical properties of trabecular bone under different strain rates was investigated. Ultrasound velocity (UV) and broadband attenuation (BUA) were measured for 60 specimens of human trabecular bone. Samples were divided into two equal groups and loaded in compression at the strain rates of 0.0004 and 0.08 s-1. The ultimate strength, elastic modulus, and energy absorption capacity were determined for each specimen. Specimens tested at 0.08 s-1 had a mean value of strength 63% higher than the specimens tested at 0.0004 s-1. The elastic modulus and energy absorption capacity were 82% and 42% higher, respectively, for the higher strain rate. UV and BUA were significantly associated with most mechanical properties at both strain rates. All mechanical properties were also correlated strongly with a linear combination of UV and BUA for both the low and high loading rates. The use of ultrasound parameters may provide good clinical means for assessing the resistance of trabecular bone to both low and high energy trauma.
Aged↗
Monoamine-induced apoptotic neuronal cell death.
1. The monoamines dopamine (DA), norepinephrine (NE), epinephrine (E), and serotonin (5-HT) serve as endogenous neurotransmitters in the nervous system. We recently reported that the neurotransmitter DA can trigger apoptosis (programmed cell death; PCD) in cultured, postmitotic chick embryo sympathetic neurons, suggesting a role for apoptosis in degenerative processes such as Parkinson's disease (PD). However, PD is also associated with involvement of other monoaminergic (MA) neuronal systems (noradrenergic and serotoninergic), though to a lesser extent. 2. We therefore tested the apoptosis-triggering potential of NE, E, and 5-HT in comparison to the DA effect, in cultured postmitotic nerve growth factor (NGF)-dependent chick embryo sympathetic neurons and mouse cerebellar granule cells. 3. In both model systems MA induced neuronal attrition characteristic of apoptosis. MA caused marked morphological alterations: severe neuronal soma shrinkage, membrane blebbing, nuclear condensation and fragmentation, and axonal disintegration. Flow-cytometric analysis of propidium iodide-stained cell nuclei revealed characteristic apoptotic nuclear fragmentation. MA-induced apoptosis could be blocked by SH-group containing antioxidants but not by inhibitors of transcription and translation. 4. Comparison between the two model systems revealed that the cerebellar granule neurons were distinctly more sensitive to the neurotoxic potential of the MA than sympathetic neuronal cells. Significant differences in the dose dependencies and time course of the apoptotic effect were observed among the examined MA, graded as DA > NE approximately E > 5-HT. 5. We conclude that the apoptosis triggering potential, probably mediated by oxidative metabolites, is shared by all MA tested, but with differential time course and dose dependencies. A correlation can be drawn between the effects of DA vs NE vs 5-HT and the relative involvement of dopaminergic/noradrenergic/serotoninergic pathways in PD, which may suggest a common multisystem underlying abnormality in neuronal apoptosis-control mechanisms.
Animals↗
Dopamine-induced apoptosis is inhibited in PC12 cells expressing Bcl-2.
1. Degeneration of nigrostriatal dopaminergic neurons is the major pathogenic substrate of Parkinson's disease (PD). It is assumed that the lethal trigger is the accumulation of oxidative reactive species generated during metabolism of the natural neurotransmitter dopamine. 2. We have recently shown that dopamine is capable of inducing programmed cell death (PCD) or apoptosis in cultured postmitotic chick sympathetic neurons and rat PC12 pheochromocytoma cells. 3. The bcl-2 gene encodes a protein which blocks physiological PCD in many mammalian cells. In an attempt to elucidate further the mechanism of dopamine toxicity, we examined the potential protective effect of bcl-2 in PC12 cells which were transfected with the protooncogene. 4. In our experiments, Bcl-2 producing cells showed a marked resistance to dopamine toxicity. The percentage of nuclear condensation and DNA fragmentation visualized by the end-labeling method following dopamine treatment was significantly lower in bcl-2 expressing cells. Bcl-2 did not protect PC12 cells against toxicity induced by exposure to dopamine-melanin. Extracts of PC12 cells containing Bcl-2 inhibited dopamine autooxidation and formation of dopamine-melanin. Furthermore, the presence of Bcl-2 protected cells from thiol imbalance and prevented thiol loss following exposure to dopamine. 5. The protective effects of Bcl-2 against dopamine toxicity may be explained, in part, by its action as an antioxidant and by its interference in the production of toxic agents. The possible protection by Bcl-2 against neuronal degeneration caused by dopamine may play a role in the pathogenesis of PD and may provide a new direction for the development of neuroprotective therapies.
Animals↗
The proto-oncogene Bcl-2 inhibits cellular toxicity of dopamine: possible implications for Parkinson's disease.
It is currently believed that excessive oxidant stress induced by metabolism of dopamine (DA), plays a major role in the pathogenesis of the selective nigrostriatal neuronal loss in Parkinson's disease. We recently showed that the neurotransmitter DA, in physiological concentrations, is capable of initiating apoptosis in cultured, post-mitotic sympathetic neurons. Bcl-2 is a proto-oncogene that blocks apoptosis. We now report that Bcl-2 is a powerful inhibitor of DA toxicity in PC-12 pheochromocytoma cells. We induced stable expression of Bcl-2 in PC-12 cells by transfection with recombinant pCMV5 expression vector, containing mouse bcl-2 (coding-sequence) cDNA. Cells expressing Bcl-2 manifested marked resistance to otherwise lethal (300 uM) in vitroconcentrations of DA. This protective effect was reflected in the trypan-blue test of cell survival, 3 H-thymidine incorporation and inhibition of the characteristic apoptotic morphologic alterations in scanning electron microscopic studies. Bcl-2 and associated control systems of apoptosis may have an important physiological role in restraining the apop-tosis-triggering potential of DA in nigrostriatal neurons. This novel field of research may yield insights into the pathogenesis of Parkinson's disease and lead to development of novel therapeutic approaches.
Journal Article↗