| 1. |
- Iancu, Ruxandra, et al.
(författare)
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Behavioral characterization of a unilateral 6-OHDA-lesion model of Parkinson's disease in mice.
- 2005
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Ingår i: Behavioural Brain Research. - : Elsevier BV. - 0166-4328. ; 162:1, s. 1-10
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Tidskriftsartikel (refereegranskat)abstract
- Parkinson's disease (PD) is one of the most common neurodegenerative disorders. Several toxin-induced animals models simulate the motor deficits occurring in PD. Among them, the unilateral 6-hydroxydopamine (6-OHDA) model is frequently used in rats and has the advantage of presenting side-biased motor impairments. However, the behavioral consequences of a unilateral 6-OHDA-lesion have, so far, not been described in detail in mice. The aim of this study was to characterize mice with unilateral 6-OHDA-lesions placed in the median forebrain bundle using several motor behavioral tests in order to identify the most suitable predictor of nigral cell loss. Mice underwent various drug-induced (amphetamine- and apomorphine-induced rotation) and spontaneous motor tests (cylinder, rotarod, elevated body swing, and stride length test). The amphetamine-induced rotation test, the cylinder and the rotarod test were most sensitive and reliable in detecting loss of tyrosine hydroxylase-immunoreactive cells in the substantia nigra. This study demonstrates that substantial and stable unilateral 6-OHDA-induced lesions can be established in mice, and that these lesions can be functionally assessed using several different side-bias-based behavioral tests. This mouse model offers the opportunity to use transgenic mouse strains and study the interactions between genes of interest and toxins in relation to Parkinson's disease etiology in the future.
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| 2. |
- Araujo, IM, et al.
(författare)
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Calpain activation is involved in early caspase-independent neurodegeneration in the hippocampus following status epilepticus
- 2008
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 105:3, s. 666-676
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Tidskriftsartikel (refereegranskat)abstract
- Evidence for increased calpain activity has been described in the hippocampus of rodent models of temporal lobe epilepsy. However, it is not known whether calpains are involved in the cell death that accompanies seizures. In this work, we characterized calpain activation by examining the proteolysis of calpain substrates and in parallel we followed cell death in the hippocampus of epileptic rats. Male Wistar rats were injected with kainic acid (KA; 10 mg/kg) intraperitoneally and sacrificed 24h later, after development of grade 5 seizures. We observed a strong Fluoro-Jade labelling in the CA1 and CA3 areas of the hippocampus in the rats that received KA, as compared to saline-treated rats. Immunohistochemistry and Western blot analysis for the calpain-derived breakdown products of spectrin (SBDP) showed evidence of increased calpain activity in the same regions of the hippocampus where cell death is observed. No evidence was found for caspase activation, in the same conditions. Treatment with the calpain inhibitor MDL 28170 significantly prevented the neurodegeneration observed in CA1. Taken together, our data suggest that early calpain activation, but not caspase activation, is involved in neurotoxicity in the hippocampus after status epilepticus.
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| 3. |
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| 4. |
- Bastlund, JF, et al.
(författare)
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Measurement of cortical and hippocampal epileptiform activity in freely moving rats by means of implantable radiotelemetry
- 2004
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Ingår i: Journal of Neuroscience Methods. - : Elsevier BV. - 1872-678X .- 0165-0270. ; 138:1-2, s. 65-72
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Tidskriftsartikel (refereegranskat)abstract
- Implanted radiotelemetry has been used for the measurement of cortical electroencephalogram (EEG), locomotor activity, body temperature and cardiovascular parameters. This technique allows high quality data acquisition from freely moving animals with no complications of externalised apparatus. This paper focuses on the methodology for short and long-term monitoring of epileptiform activity by simultaneous cortical EEG, hippocampal (HC) EEG and electromyogram (EMG) in rats. The circadian rhythm of temperature (CRT) was monitored after surgery to estimate the need for post surgical recovery of animals. Different placements of EMG electrodes were assessed in order to minimise artefacts and increase sensitivity. The occurrence of epileptiform ictal and interictal activity following an acute injection of either 40 mg/kg pentylenetetrazole (PTZ) or 13.8 mg/kg kainic acid (KA) was investigated. The occurrence of spontaneous seizures was also monitored 5-8 weeks after administration of KA. The present study demonstrated a sensitive method for monitoring cortical EEG, hippocampal EEG and EMG short and long-term by implantable radiotelemetry in freely moving rats.
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| 5. |
- Bastlund, JF, et al.
(författare)
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Spontaneous epileptic rats show changes in sleep architecture and hypothalamic pathology
- 2005
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Ingår i: Epilepsia. - : Wiley. - 0013-9580 .- 1528-1167. ; 46:6, s. 934-938
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The goal of the present study was to investigate the relationship between sleep, hypothalamic pathology, and seizures in spontaneous epileptic rats. Methods: Rats were implanted with radiotelemetry transmitters for measuring electrocorticogram (ECoG) and stimulation electrodes in the hippocampus. Epileptogenesis was triggered by 2 h of electical stimulation-induced self-sustained status epilepticus (SSSE). After SSSE, ECoGs were monitored over a 15-week period for the occurrence of interictal high-amplitude low-frequency (HALF) activity and spontaneous reoccurring seizures (SRSs). Results: Spontaneous epileptic rats showed clinical features of temporal lobe epilepsy (TLE), such as spontaneous seizures, interictal activity and neuronal cell loss in the dorsomedial hypothalamus, a region important for normal sleep regulation. Interestingly, epileptic rats showed disturbances in sleep architecture, with a high percentage of the seizures occurring during sleep. Conclusions: Therefore we conclude that a close association exists between epileptiform activity and alterations in sleep architecture that may be related to hypothalamic pathology.
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| 6. |
- Bengzon, Johan, et al.
(författare)
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Neuronal apoptosis after brief and prolonged seizures.
- 2002
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Ingår i: Progress in Brain Research. - 1875-7855. ; 135, s. 111-119
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Forskningsöversikt (refereegranskat)abstract
- Evidence has accumulated that apoptotic cell death contributes to brain damage following experimental seizures. A substantial number of degenerating neurons within limbic regions display morphological features of apoptosis following prolonged seizures evoked by systemic or local injections of kainic acid, systemic injections of pilocarpine and sustained stimulation of the perforant path. Although longer periods of seizures consistently result in brain damage, it has previously not been clear whether brief single or intermittent seizures lead to cell death. However, recent results indicate that also single seizures lead to apoptotic neuronal death. A brief, non-convulsive seizure evoked by kindling stimulation was found to produce apoptotic neurons bilaterally in the rat dentate gyrus. The mechanism triggering and mediating apoptotic degeneration is at present being studied. Alterations in the expression and activity of cell-death regulatory proteins such as members of the Bcl-2 family and the cysteinyl aspartate-specific proteinase (caspase) family occur in regions vulnerable to cell degeneration, suggesting an involvement of these factors in mediating apoptosis following seizures. Findings of decreased apoptotic cell death following administration of caspase inhibitors prior to and following experimentally induced status epilepticus, further suggest a role for caspases in seizure-evoked neuronal degeneration. Intermediate forms of cell death with both necrotic and apoptotic features have been found after seizures and investigation into the detailed mechanisms of the different forms of cell degeneration is needed before attempts to specific prevention can be made.
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| 7. |
- Ekdahl, Christine T, et al.
(författare)
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Caspase inhibitors increase short-term survival of progenitor-cell progeny in the adult rat dentate gyrus following status epilepticus
- 2001
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 14:6, s. 937-945
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Tidskriftsartikel (refereegranskat)abstract
- The dentate gyrus (DG) is one of the few regions in the brain that continues to produce new neurons throughout adulthood. Seizures not only increase neurogenesis, but also lead to death of DG neurons. We investigated the relationship between cell death and neurogenesis following seizures in the DG of adult rats by blocking caspases, which are key components of apoptotic cell death. Multiple intracerebroventricular infusions of caspase inhibitors (pancaspase inhibitor zVADfmk, and caspase 3 and 9 inhibitor) prior to, just after, 1 day after, and 1 week following 2 h of lithium-pilocarpine-induced status epilepticus reduced the number of terminal deoxynucleotidyl transferase-mediated fluorescein-dUTP nick-end labelled (TUNEL) cells and increased the number of bromodeoxyuridine (BrdU) -stained proliferated cells in the subgranular zone at 1 week. The caspase inhibitor-treated group did not differ from control at 2 days or 5 weeks following the epileptic insult. Our findings suggest that caspases modulate seizure-induced neurogenesis in the DG, probably by regulating apoptosis of newly born neurons, and that this action can be suppressed transiently by caspase inhibitors. Furthermore, although previous studies have indicated that increased neuronal death can trigger neurogenesis, we show here that reduction in apoptotic death may be associated with increased neurogenesis.
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| 8. |
- Ekdahl Clementson, Christine, et al.
(författare)
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Caspase-mediated death of newly formed neurons in the adult rat dentate gyrus following status epilepticus.
- 2002
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Ingår i: European Journal of Neuroscience. - : Wiley. - 1460-9568 .- 0953-816X. ; 16:8, s. 1463-1471
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Tidskriftsartikel (refereegranskat)abstract
- A large proportion of cells that proliferate in the adult dentate gyrus under normal conditions or in response to brain insults exhibit only short-term survival. Here, we sought to determine which cell death pathways are involved in the degeneration of newly formed neurons in the rat dentate gyrus following 2 h of electrically induced status epilepticus. We investigated the role of three families of cysteine proteases, caspases, calpains, and cathepsins, which can all participate in apoptotic cell death. Status epilepticus increased the number of bromodeoxyuridine (BrdU)-positive proliferated cells in the subgranular zone of the dentate gyrus. At the time of maximum cell proliferation, immunohistochemical analyses revealed protein expression of active caspase-cleaved poly (ADP-ribose) polymerase (PARP) in approximately 66% of the BrdU-positive cells, while none of them expressed cathepsin B or the 150-kDa calpain-produced fodrin breakdown product. To evaluate the importance of cysteine proteases in regulating survival of the newly formed neurons, we administered intracerebroventricular infusions of a caspase inhibitor cocktail (zVAD-fmk, zDEVD-fmk and zLEHD-fmk) over a 2-week period, sufficient to allow for neuronal differentiation, starting 1 week after the epileptic insult. Increased numbers of cells double-labelled with BrdU and neuron-specific nuclear protein (NeuN) marker were detected in the subgranular zone and granule cell layer of the caspase inhibitor-treated rats. Our data indicate that caspase-mediated cell death pathways are active in progenitor cell progeny generated by status epilepticus and compromise survival during neuronal differentiation.
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| 9. |
- Frielingsdorf, Helena, et al.
(författare)
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No evidence for new dopaminergic neurons in the adult mammalian substantia nigra.
- 2004
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 101:27, s. 10177-10182
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Tidskriftsartikel (refereegranskat)abstract
- A recent report by Zhao et al. [Zhao, M., Momma, S., Delfani, K., Carlen, M., Cassidy, R. M., Johansson, C. B., Brismar, H., Shupliakov, O., Frisen, J. & Janson, A. M. (2003) Proc. Natl. Acad. Sci. USA 100, 7925–7930] suggests that dopaminergic neurons, the cell type lost in Parkinson's disease, are continuously generated in the adult substantia nigra pars compacta. Using similar methodological procedures to label dividing cells, we found no evidence of new dopaminergic neurons in the substantia nigra, either in normal or 6-hydroxydopamine-lesioned hemi-Parkinsonian rodents, or even after growth factor treatment. Furthermore, we found no evidence of neural stem cells emanating from the cerebroventricular system and migrating to the substantia nigra. We conclude that it is unlikely that dopaminergic neurons are generated in the adult mammalian substantia nigra.
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| 10. |
- Gil, Joana, et al.
(författare)
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Reduced hippocampal neurogenesis in R6/2 transgenic Huntington's disease mice.
- 2005
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Ingår i: Neurobiology of Disease. - : Elsevier BV. - 0969-9961. ; 20:3, s. 744-751
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Tidskriftsartikel (refereegranskat)abstract
- We investigated whether cell proliferation and neurogenesis are altered in R6/2 transgenic Huntington's disease mice. Using bromodeoxyuridine (BrdU), we found a progressive decrease in the number of proliferating cells in the dentate gyrus of R6/2 mice. This reduction was detected in pre-symptomatic mice, and by 11.5 weeks, R6/2 mice had 66% fewer newly born cells in the hippocampus. The results were confirmed by immunohistochemistry for the cell cycle markers Ki-67 and proliferating cell nuclear antigen (PCNA). We did not observe changes in cell proliferation in the R6/2 subventricular zone, indicating that the decrease in cell proliferation is specific for the hippocampus. This decrease corresponded to a reduction in actual hippocampal neurogenesis as assessed by double immunostaining for BrdU and the neuronal marker neuronal nuclei (NeuN) and by immunohistochemistry for the neuroblast marker doublecortin. Reduced hippocampal neurogenesis may be a novel neuropathological feature in R6/2 mice that could be assessed when evaluating potential therapies.
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