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David Porquet,
Gemma Casadesús,
Sergi Bayod,
Alberto Vicente, Anna M Canudas,
Jordi Vilaplana,
Carme Pelegrí,
Coral Sanfeliu,
Antoni Camins,
Mercè Pallàs,
Jaume Del Valle
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ABSTRACT: Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that long-term dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.
Age 11/2012; · 6.28 Impact Factor
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ABSTRACT: Exercise enhances general health. However, its effects on neurodegeneration are controversial, and the molecular pathways in the brain involved in this enhancement are poorly understood. Here, we examined the effect of long-term moderate treadmill training on adult male rat cortex and hippocampus to identify the cellular mechanisms behind the effects of exercise. We compared three animal groups: exercised (30 min/day, 12 m/min, 5 days/wk, 36 wk), handled but nonexercised (treadmill handling procedure, 0 m/min), and sedentary (nonhandled and nonexercised). Moderate long-term exercise induced an increase in IGF-1 levels and also in energy parameters, such as PGC-1α and the OXPHOS system. Moreover, the sirtuin 1 pathway was activated in both the exercised and nonexercised groups but not in sedentary rats. This induction could be a consequence of exercise as well as the handling procedure. To determine whether the long-term moderate treadmill training had neuroprotective effects, we studied tau hyperphosphorylation and GSK3β activation. Our results showed reduced levels of phospho-tau and GSK3β activation mainly in the hippocampus of the exercised animals. In conclusion, in our rodent model, exercise improved several major brain parameters, especially in the hippocampus. These improvements induced the upregulation of sirtuin 1, a protein that extends life, the stimulation of mitochondrial biogenesis, the activation of AMPK, and the prevention of signs of neurodegeneration. These findings are consistent with other reports showing that physical exercise has positive effects on hormesis.
Journal of Applied Physiology 08/2011; 111(5):1380-90. · 3.75 Impact Factor
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ABSTRACT: We investigated the neuroprotective effects of lithium in an experimental neurodegeneration model gated to kainate (KA) receptor activation.
The hippocampus from KA-treated mice and hippocampal cell cultures were used to evaluate the pathways regulated by chronic lithium pretreatment in both in vivo and in vitro models.
Treatment with KA, as measured by fragmentation of alpha-spectrin and biochemically, induced the activation of calpain resulting in p35 cleavage to p25, indicating activation of cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase-3ss (GSK-3ss) and an increase in tau protein phosphorylation. Treatment with lithium reduced calpain activation and reduced the effects of cdk5 and GSK-3ss on tau. KA treatment of cultures resulted in neuronal demise. According to nuclear condensed cell counts, the addition of lithium to neuronal cell cultures (0.5-1 mM) a few days before KA treatment had neuroprotective and also antiapoptotic effects. The action of lithium on calpain/cdk5 and GSK-3ss pathways produced similar results in vivo. As calpain is activated by an increase in intracellular calcium, we showed that lithium reduced calcium concentrations in basal and KA-treated hippocampal cells, which was accompanied by an increase in NCX3, a Na+/Ca2+ exchanger pump.
A robust neuroprotective effect of lithium in the excitotoxic process induced by KA in mouse hippocampus was demonstrated via modulation of calcium entry and the subsequent inhibition of the calpain pathway. These mechanisms may act in an additive way with other mechanisms previously described for lithium, suggesting that it may be useful as a possible therapeutic strategy for Alzheimer's disease.
Bipolar Disorders 06/2010; 12(4):425-36. · 5.29 Impact Factor
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ABSTRACT: Lithium is a simple cation that has been used clinically since 1950 for the treatment of bipolar disorder. However in the last decade numerous studies either using animal models or human trials suggest that this cation may delay progression of neurodegenerative diseases. One of the main challenges facing researchers in the neurosciences is to identify key molecules in neuronal apoptosis. This would facilitate the identification of targets in order to design drugs for the treatment of Alzheimer's disease, Parkinson's disease and other neurological disorders. Although enormous effort has been made in the past few years and it has been demonstrated that the mitochondria comprise a key component of the neuronal apoptotic route, it seems that in addition to the mitochondria other intracellular components are implicated in this process. It has been proposed that DNA damage and re-entry into the cell cycle or the activation of different proteases, such as calpain, could constitute a common pathway in the apoptotic process and thus death processes in neurological diseases. The hypothesis about the implication of calpain in neuronal cell death is supported by existing data on neurodegenerative disorders in the brains of patients who show an increase in proteolytic activity of calpain compared with control brains. Indeed, studies performed in neuronal cell preparations suggest that activation of this protease is accompanied by other features such as structural modifications of the cytoskeleton, cleavage of several receptors, activation of kinases, such as cdk5 or GSK3ss, etc. Here, we summarize the potential routes involved in neurodegenerative disorders related to calpain activation, mainly those connected with changes in calcium homeostasis machinery, activation of kinase pathways, transcription factors, and the cell cycle.
Current Drug Metabolism 09/2009; 10(5):433-47. · 5.11 Impact Factor
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ABSTRACT: 3-Nitropropionic acid (3-NP) is a neurotoxin that inhibits mitochondrial complex II and is used in an experimental model of Huntington's disease. Treatment of rats with 3-NP 30mgkg(-1) i.p. once a day for 5 days induced an increase in calpain activation in rat striatum, measured by the formation of 145kDa fragment of alpha-spectrin breakdown and by an increase in enzymatic calpain activity. In this neurotoxic model, Western blot studies revealed that calpain activity increase was followed by changes in cyclin-dependent kinase 5 (cdk5) and its activator p25. Our results indicated, after 10 days of treatment with 3-NP, a decrease in myocyte enhancer factor phosphorylation, a neuronal prosurvival factor. Thus, a decrease in its expression indicates a new potential mechanism of neuronal cell death mediated by the neurotoxin 3-NP. Accordingly, in our study we demonstrated in rat striatum the activation of the calpain/cdk5/p25 pathway in the 3-NP model. Previous studies have linked the deregulation of cdk5 with neurodegenerative diseases, such as Alzheimer's and Parkinson's. We suggest that calpain/cdk5 activation could also be a common pathway activated in other neurodegenerative diseases, which is liable to be targeted.
Neuroscience Letters 07/2007; 421(1):77-81. · 2.11 Impact Factor
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ABSTRACT: Certain effects of melatonin on senescence were investigated. The experimental model used was 10-month-old senescence-accelerated mouse prone 8 (SAMP8). The mice in the experiment were administered melatonin (10 mg/kg) from the age of 1 month. Results showed that chronic administration of melatonin decreased cell loss in the cerebral cortex and reduced oxidative damage in protein and lipids. There are several studies suggesting that the activation of the cdk5/p35 pathway at its cleavage to cdk5/p25 may play a role in hyperphosphorylation of tau during aging and neurodegenerative diseases. Melatonin not only reduced the cerebral aging disturbances, but also prevented tau hyperphosphorylation present in the experimental model used in this study. Melatonin reduced cdk5 expression, as well as the cleavage of p35 to p25. The other tau kinase studied, GSK3beta, showed a reduction in this activity in comparison with SAMP8 nontreated SAMP8. These data indicate that melatonin possesses neuroprotective properties against cerebral damage gated to senescence. Moreover, these data suggest that the cdk5/GSKbeta signaling cascade has a potential role as a target for neurodegenerative diseases related to aging.
Journal of Pineal Research 05/2007; 42(4):394-402. · 5.79 Impact Factor
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ABSTRACT: Tau is a neuronal microtubule-associated protein found predominantly on axons. Tau phosphorylation regulates both normal and pathological functions of this protein. Hyperphosphorylation impairs the microtubule binding function of tau, resulting in the destabilization of microtubules in brain, ultimately leading to the degeneration of the affected neurons. Numerous serine/threonine kinases, including GSK-3beta and Cdk5 can phosphorylate tau. SAMR1 and SAMP8 are murine strains of senescence. We show an increase in hyperphosphorylated forms of tau in SAMP8 (senescent mice) in comparison with resistant strain SAMR1. Moreover, an increase in Cdk5 expression and activation is described but analysis of GSK3beta isoforms failed to show differences in SAMP8 in comparison to age-matched SAMR1. In conclusion, tau hyperphosphorylation occurs in SAMP-8 (early senescent) mice, indicating a link between aging and tau modifications in this murine model.
Mechanisms of Ageing and Development 01/2006; 126(12):1300-4. · 3.44 Impact Factor
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ABSTRACT: The pharmacological treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis (ALS) currently represents a major medical challenge. The mechanisms involved in the apoptotic neuronal cell death, associated with such disorders, are still not clear, but recent data suggest that cyclindependent kinases (CDKs) play a prominent role (Liu et al., 2003). Canonical CDKs such as CDK2 and CDK4/CDK6 are enzymes associated with cyclin regulatory subunits that control cell cycle progression. The evidence that neurons in postmortem brain tissue from patients with neurodegenerative diseases express CDKs, supports to the hypothesis that re-entry into the cell cycle could be an apoptotic pathway involved in the neurodegenerative process. Several authors suggest that the transcription factor E2F-1 function as a link between the cell cycle and apoptosis in neurons. Additionally the expression of CDK5 has been demonstrated in postmortem brain tissue from patients with neurodegenerative diseases. CDK5 is an atypical CDK, that does not require association with a cyclin and is not implicated in the cell cycle progression. Instead, it is associated with the neuronal co-activators p35 and p39, and is required for neuronal development, axonal outgrowth, learning and memory. Recent evidence also points to a leading role for CDK5/p25 in apoptosis and neurodegeneration. CDK inhibitors such as flavopiridol and roscovitine are being developed and tested in clinical trials as novel antineoplasic agents. Thus, due to the implication of CDKs in neuronal apoptosis, a new application of these drugs in the treatment of neurodegenerative diseases is suggested.
Current Medicinal Chemistry - Central Nervous System Agents 05/2005; 5(2):101-109.
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ABSTRACT: Injury to the central nervous system causes atrophy or death of connecting neurons and can modify the expression of neurotrophic factors. We observed transneuronal upregulation of brain-derived neurotrophic factor (BDNF) expression in the rat ipsilateral substantia nigra pars compacta after a striatal lesion induced by kainate. This effect is developmentally regulated because the enhancement of nigral BDNF expression was only observed when striatal lesion was performed on postnatal day (P) 15 and in adulthood, but not at P7. Interestingly, the lack of regulation of BDNF was coincident with the transynaptic degeneration of nigral neurons after striatal excitotoxic injury. Hence, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta decreased when the lesion was performed at P7, but not at P15 or at P30. The analysis of the functional significance of this BDNF upregulation was done using trkB-IgG fusion proteins. After striatal injury, blockade of endogenous BDNF by trkB fusion proteins induced an atrophy of the dopaminergic neurons of the pars compacta. The injection of trkB-IgG fusion proteins did not modify the effects of kainate in the substantia nigra pars reticulata. Thus, our results show that BDNF exerts an autocrine/paracrine protective effect selectively on dopaminergic neurons against the loss of trophic support from the target striatum.
Molecular Brain Research 04/2005; 134(1):147-54. · 2.00 Impact Factor
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ABSTRACT: The neurotoxic action of the abuse drugs methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA) on cerebellar granule neurones (CGNs) culture was examined. Treatment for 48 h with METH or MDMA (1-5 mM) induced a higher decrease in viability than 24 h treatment. z.VAD.fmk (100 microM) but not MK-801 nor NBQX recovered control viability values. In both cases, cell death was characterised as apoptotic rather than necrotic by morphology cell observation. Apoptosis measured by flow cytometry indicated an increase in the hypodiploid population after 48 h treatment with METH and MDMA. Apoptosis was reverted by the presence of z.VAD.fmk (100 microM) but not by 10 microM MK-801 or NBQX. Similar results were obtained by analysing nuclear chromatine condensation. These results ruled out excitotoxic participation in amphetamine derivative-induced neurotoxicity in CGNs. Participation of radical oxygen species (ROS) was evaluated using alpha-tocopherol (1-15 microM) and cytometric studies. The co-treatment with 4 mM METH or MDMA for 48 h partially reverted neurotoxic action and apoptotic features, indicating ROS implication in CGNs death by amphetamine derivatives. Alteration of mitochondrial function induced cytochrome C (Cyt C) release after 48-h treatment with METH and MDMA (4 mM). There was also indication of caspase-3-like activation, measured by immunoanalysis and biochemically. Finally, neurodegenerative action caused by amphetamine derivatives may be prevented by using caspase inhibitors.
Toxicology and Applied Pharmacology 05/2004; 196(2):223-34. · 4.45 Impact Factor
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ABSTRACT: Neuronal apoptosis may be partly due to inappropriate control of the cell cycle. We used serum deprivation as stimulus and reduced potassium from 25 to 5mM (S/K deprivation), which induces apoptosis in cerebellar granule neurons (CGNs), to evaluate the direct correlation between re-entry in the cell cycle and apoptosis. Roscovitine (10 microM), an antitumoral drug that inhibits cyclin-dependent kinase 1 (cdk1), cdk2 and cdk5, showed a significant neuroprotective effect on CGNs deprived of S/K. S/K deprivation induced the expression of cell cycle proteins such as cyclin E, cyclin A, cdk2, cdk4 and E2F-1. It also caused CGNs to enter the S phase of the cell cycle, measured by a significant incorporation of BrdU (30% increase over control cells), which was reduced in the presence of roscovitine (10 microM). On the other hand, roscovitine modified the expression of cytochrome c (Cyt c), Bcl-2 and Bax, which are involved in the apoptotic intrinsic pathway induced by S/K deprivation. We suggest that the antiapoptotic effects of roscovitine on CGNs are due to its anti-proliferative efficacy and to an action on the mitochondrial apoptotic mechanism.
Neurochemistry International 04/2004; 44(4):251-61. · 2.86 Impact Factor
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ABSTRACT: Kainic acid (KA)-induced neuronal damage and the protective effects of flavopiridol were studied in primary cultures of rat cerebellar granule cells (CGNs). When neurons were treated with 500 microM KA, the percentage of cells with condensed nuclei measured by nuclear counting increased by up to 55%. After flavopiridol treatment, an antitumoral drug that is a broad inhibitor of cyclin-dependent kinases, the percentage of condensed nuclei decreased by up to 26%. Furthermore, this KA-mediated cell death was only partially dependent on the activation of the initiator caspase-9 and the effector caspases-3 and -6. This argues for a minor role of caspases in the intracellular pathway leading to KA-induced programmed cell death in CGNs. We examined the possible implication of cell cycle proteins in KA-induced neurotoxicity. We found an increase in the expression of proliferating cell nuclear antigen and E2F-1, two proteins implicated in S-phase, by Western blot. KA increased bromodeoxyuridine incorporation in CGNs, a marker of cell proliferation, and flavopiridol attenuated this effect. These results indicated that flavopiridol decreased the expression of cell cycle markers in CGNs after KA treatment. Flavopiridol might thus be used as a preventive agent against neurodegenerative diseases associated with cell cycle activation.
Journal of Pharmacology and Experimental Therapeutics 03/2004; 308(2):609-16. · 3.83 Impact Factor
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ABSTRACT: Stimulation of ionotropic glutamate receptors are implicated in neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Recently this has been demonstrated in the expression of cell cycle proteins in vulnerable neurons in Alzheimer's disease. Thus, the aim of the present study was to evaluate the expression of cell cycle proteins in cerebellar granule cells after stimulation of AMPA/KA receptors and likewise to study the neuroprotective effects of CDK inhibitors. Our results demonstrated that after a treatment with CDK inhibitors, a significant decrease in apoptotic nuclei induced by kainic acid was found in the presence of flavopiridol and 3-ATA. We concluded that CDK activation is involved, at least, in part, in the pro-apoptotic effects of kainic acid.
Annals of the New York Academy of Sciences 01/2004; 1010:671-4. · 3.15 Impact Factor
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Elvira G Jorda,
Ester Verdaguer, Anna M Canudas,
Andrés Jiménez,
Alejandra Bruna,
Carme Caelles,
Ramona Bravo,
Elena Escubedo,
David Pubill,
Jordi Camarasa,
Mercè Pallàs,
Antoni Camins
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ABSTRACT: Flavopiridol was developed as a drug for cancer therapy due to its ability to inhibit cell cycle progression by targeting cyclin-dependent kinases (CDKs). In this study, we show that flavopiridol may also have a neuroprotective action. We show that at therapeutic dosage (or at micromolar range), flavopiridol almost completely prevents colchicine-induced apoptosis in cerebellar granule neurones. In agreement with this, flavopiridol inhibits both the release of cyt c and the activation of caspase-3 induced in response to colchicine treatment. We demonstrate that in this cellular model for neurotoxicity, neither re-entry in the cell cycle nor activation of stress-activated protein kinases, such as c-Jun N-terminal kinase (JNK) or p38 MAP kinase, is involved. In contrast, we show that colchicine-induced apoptosis correlates with a substantial increase in the expression of cdk5 and Par-4, which is efficiently prevented by flavopiridol. Accordingly, a cdk5 inhibitor such as roscovitine, but not a cdk4 inhibitor such as 3-ATA, was also able to protect neurons from apoptosis as well as prevent accumulation of cdk5 and Par-4 in response to colchicine. Our data suggest a potential therapeutic use of flavopiridol in disorders of the central nervous system in which cytoskeleton alteration mediated by cdk5 activation and Par-4 expression has been demonstrated, such as Alzheimer's disease.
Neuropharmacology 11/2003; 45(5):672-83. · 4.81 Impact Factor
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ABSTRACT: The consequences of the neurotoxic insult induced by 3,4-methylenedioxymethamphetamine (MDMA, an amphetamine derivative with specific action on the serotonergic system) were compared with those of methamphetamine (a derivative with specific action on dopaminergic system) in rats. Both drugs induced a very similar loss of body weight, especially evident 24 h after treatment. Their hyperthermic profile was also very similar and was dependent on ambient temperature, corroborating the thermo-dysregulatory effect of both substances. Methamphetamine (four injections of 10 mg kg(-1) s.c. at 2-h intervals) induced the loss of dopaminergic (35%) but not of serotonergic, terminals in the rat striatum and, simultaneously, a significant increase in striatal peripheral-type benzodiazepine receptor density, pointing to a glial reaction. Evidence for this drug-induced astrogliosis was the increased heat shock protein 27 (HSP27) expression in striatum, cortex and hippocampus. MDMA (20 mg kg(-1) s.c. b.i.d. for 4 days) induced a similar dopaminergic lesion in the striatum 3 days post-treatment, which reversed 4 days later. An important neurotoxic effect on serotonergic terminals was also observed in the cortex, striatum and hippocampus 3 days post-treatment, which partially reversed 4 days later in the striatum and hippocampus. No microglial activation was noticeable at either 3 or 7 days after MDMA treatment. This lack of effect on microglial cells was assessed by [(3)H]PK 11195 binding and OX-6 immunostaining, which were unchanged in the striatum and cortex after MDMA treatment. A non-significant tendency to increase was noted in the hippocampus 3 days after MDMA treatment. Furthermore, in MDMA-treated rats, neither HSP27 expression nor an increase in HSP27 immunoreactivity were detected. This result, together with the lack of increase in glial fibrilliary acidic protein (GFAP) immunoreactivity, indicate no astroglial activation at either 3 or 7 days post-treatment. Without microglial activation, an inflammatory process would not accompany the lesion induced by MDMA. The differences in glial activation between methamphetamine and MDMA observed in the present study could have implications for the prognosis of the injury induced by these drugs.
Archiv für Experimentelle Pathologie und Pharmakologie 06/2003; 367(5):490-9. · 2.65 Impact Factor
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ABSTRACT: We have investigated the neuroprotective effects of (+/-)-huprine Y on excitotoxic lesions in rat cerebellar granule cells (CGCs). (+/-)-Huprine Y prevented cell death induced by 100 microM glutamate, as well as, 10 microM MK-801, a NMDA receptor antagonist, in a significant manner. On the other hand, intracellular calcium increase induced by NMDA (200 microM), measured by fura-2 fluorescence, was prevented by (+/-)-huprine Y with an EC(50) of 12.44 microM, which evidences the modulatory action of this compound on NMDA-induced calcium currents. In vivo, we have studied (+/-)-huprine Y neuroprotective effects on striatal lesions induced by the subacute administration of the mitochondrial toxin 3-nitropropionic acid (3-NP, 30 mg/kg, ip, for 10 days). We have assessed that both the behavioral and the morphological consequences of the lesion were prevented by pretreatment with (+/-)-huprine Y (2.5 mg/kg/twice a day, ip). Striatal gliosis induced by 3-NP treatment was prevented by (+/-)-huprine Y pretreatment, as demonstrated by the attenuation of both the increase in [(3)H]PK 11195 specific binding indicative of microgliosis and the expression of hsp27 kDa, a chaperone expressed mainly in astrocytes. In conclusion, (+/-)-huprine Y attenuated excitotoxic-induced lesions, both in vitro and in vivo, and further evidence is provided for the potential use of this compound in the prevention of neurodegenerative disorders.
Experimental Neurology 05/2003; 180(2):123-30. · 4.70 Impact Factor
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ABSTRACT: Glial cell line-derived neurotrophic factor (GDNF) family ligands are important regulators of neuronal development and maintenance of the connectivity in the basal ganglia and show neuroprotective activities in several paradigms of brain injury. The mRNAs of two members of this family, GDNF and neurturin, and also their receptors have been detected in the basal ganglia. In the present work, we analyzed the time course changes in the expression of these neurotrophic factors and receptors in the adult rat striatum, induced by quinolinate or kainate excitotoxicity. Our results show that stimulation of NMDA or non-NMDA receptors induced different effects on the mRNA levels analyzed. Expression of GDNF and its preferred receptor, GDNF family receptor-alpha1 (GFRalpha1), was transiently up-regulated by quinolinate and kainate, but with differing intensity and temporal pattern. Immunohistochemical analysis showed that, although GDNF and GFRalpha1 were initially localized in neurons, excitotoxicity induced the expression of these proteins in astrocyte-like cells. Neurturin mRNA levels were only up-regulated after quinolinate injection, whereas quinolinate or kainate injection did not modify GFRalpha2 mRNA. The mRNA for the common receptor, c-Ret, was up-regulated by both agonists with similar temporal pattern but with differing intensity. Immunohistochemical analysis showed that c-Ret protein was located on neurons. These changes in mRNA levels and protein localization of GDNF family components could reflect an endogenous trophic response of striatal cells to different excitotoxic insults.
Experimental Neurology 05/2002; 174(2):243-52. · 4.70 Impact Factor
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ABSTRACT: 1. We examined the role of non-NMDA receptors in kainic acid (KA)-induced apoptosis in cultures of rat cerebellar granule cells (CGCs). KA (1 - 500 microM) induced cell death in a concentration-dependent manner, which was prevented by NBQX and GYKI 52466, non-NMDA receptor antagonists. Moreover, AMPA blocked KA-induced excitotoxicity, through desensitization of AMPA receptors. 2. Similarly, KA raised the intracellular calcium concentration of CGCs, which was inhibited by NBQX and GYKI 52466. Again, AMPA (100 microM) abolished the KA (100 microM)-induced increase in intracellular calcium concentration. 3. KA-induced cell death in CGCs had apoptotic features, which were determined morphologically, by DNA fragmentation, and by expression of the prostate apoptosis response-4 protein (Par-4). 5. KA (500 microM) slightly (18%) increased caspase-3 activity, which was strongly enhanced by colchicine (1 microM), an apoptotic stimulus. However, neither Z-VAD.fmk, a pan-caspase inhibitor, nor the more specific caspase-3 inhibitor, Ac-DEVD-CHO, prevented KA-induced cell death or apoptosis. In contrast, both drugs inhibited colchicine-induced apoptosis. 5. The calpain inhibitor ALLN had no effect on KA or colchicine-induced neurotoxicity. 6. Our findings indicate that colchicine-induced apoptosis in CGCs is mediated by caspase-3 activation, unlike KA-induced apoptosis.
British Journal of Pharmacology 04/2002; 135(5):1297-307. · 4.41 Impact Factor
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ABSTRACT: This study was undertaken to investigate whether kainic acid (KA) may regulate the expression of several proteins which plays an important role in cell-cycle progression in cerebellar granule neurons (CGNs). KA induced decrease in MTT values in a concentration dependent way. Flow cytometric analysis showed that KA was able to induce 30% apoptosis in CGNs. Apoptotic nuclear condensation were detected 24 h of exposure to KA (200 microM). An associated marked increase in DNA synthesis, measured by BrdU incorporation, was observed. Western blot analysis showed that KA induced an increase in the expression of Cdk2, cyclin E and E2F-1. It is proposed that, in post-mitotic cells like CGNs, re-entry cell cycle could be responsible for the apoptotic effect of KA.
Neuroreport 04/2002; 13(4):413-6. · 1.66 Impact Factor
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ABSTRACT: Injection of MPP+ into the substantia nigra causes extensive necrosis and anterograde degeneration of pars compacta dopaminergic neurons. We studied secondary effects in the ipsilateral striatum by examining dopaminergic terminals, signs of neuronal damage, and glial reactivity at 1, 2, 3, and 7 days after injection of MPP+ into the substantia nigra. Dopaminergic terminals and uptake sites were evaluated with [3H]GBR-12935 binding and tyrosine hydroxylase immunoreactivity. Glial reaction was examined with markers of astrocytes and microglia. Stereology was used to evaluate any changes in neuronal density. Tyrosine hydroxylase immunoreactivity and [3H]GBR-12935 binding markedly decreased (74%) from days 2 to 7. Loss of dopaminergic terminals in the ipsilateral striatum was accompanied by an intense astroglial and, to a lesser extent, microglial reaction. However, no signs of cell damage, neuronal loss, or disruption of the blood–brain barrier were found in the striatum. Resident astroglial and microglial cells showed a morphological shift and notable changes in protein expression typical of glial reactivity, yet the presence of macrophage-like cells was not detected. This study shows that injection of MPP+ in the substantia nigra causes a secondary reaction within the ipsilateral striatum involving the transformation of quiescent glia to reactive glia. It is suggested that stimuli derived from damaged dopaminergic terminals within the striatum are able to activate resident glia and that this glial transformation may promote repair and regeneration.
Neurobiology of Disease.
