Rotenone and 1-methyl-4-phenyl pyridinium (MPP+) are two mitochondrial neurotoxins known to produce Parkinson's disease (PD) in experimental animals. In the present study, we compared drug-induced rotational asymmetry in rats lesioned using these neurotoxins at three distinct basal ganglia sites, the striatum, substantia nigra pars compacta (SNpc) and median forebrain bundle (MFB). The levels of dopamine (DA) in the ipsilateral striata of these hemiparkinsonian animals were assayed employing an HPLC-electrochemical procedure 2 days after the final rotational study. Rats infused with rotenone or MPP+ into the SNpc, but not into the striatum or MFB, exhibited contralateral rotations immediately after recovery from anesthesia. Irrespective of the lesion site or the toxin used, all the animals exhibited ipsilateral rotations when challenged with D-amphetamine. Apomorphine administration caused contralateral circling behavior in MFB-lesioned animals, but ipsilateral rotations in rats that received rotenone or MPP+ in the striatum or SNpc. Stereotaxic administration of rotenone into the MFB, SNpc or striatum caused a significant loss of DA in the ipsilateral striatum to varying degrees (96%, 62% and 30%, respectively, as compared to the contralateral side). However, unilateral MPP+ administration into the MFB, SNpc or striatum caused respectively about 98%, 74% and 59% loss of striatal DA. Behavioural observations and the neurochemical results indicate that, among the three anatomically distinct loci-lesioned, MFB-lesioned animals mimicked behavioral aberrations similar to nigral lesions caused by 6-hydroxydopamine, a classical parkinsonian neurotoxin. Moreover, the results point out that while both d-amphetamine and apomorphine-induced rotations could be considered as valuable behavioral indices to test novel drugs against PD, yet apomorphine-induced contralateral bias proves to be a more reliable indicator of specific destruction in the nigrostriatal pathway and development of post-synaptic DA receptor supersensitivity.
"Literature reveals only a couple of reports of transplantation studies in rotenone model of PD , , which is unique in terms of its progressive nature  and protein aggregation pathology . We have chosen the site of infusion of the neurotoxin to be MFB, which induces ipsilateral or contralateral rotations when animals are challenged respectively with amphetamine or apomorphine, unlike intranigral or intrastriatal infusion of rotenone . Therefore we were assured of selective loss of nigrostriatal pathway since amphetamine and apomorphine challenge respectively is an indicator of presynaptic DA release, and postsynaptic supersensitivity, and so true signs of destruction of nigrostriatal pathway . "
[Show abstract][Hide abstract] ABSTRACT: We report here protection against rotenone-induced behavioural dysfunction, striatal dopamine depletion and nigral neuronal loss, following intra-striatal transplantation of neurons differentiated from murine embryonic stem cells (mES). mES maintained in serum free medium exhibited increase in neuronal, and decrease in stem cell markers by 7th and 10th days as revealed by RT-PCR and immunoblot analyses. Tyrosine hydroxylase, NURR1, PITX3, LMX1b and c-RET mRNA showed a significant higher expression in differentiated cells than in mES. Dopamine level was increased by 3-fold on 10th day as compared to 7 days differentiated cells. Severity of rotenone-induced striatal dopamine loss was attenuated, and amphetamine-induced unilateral rotations were significantly reduced in animals transplanted with 7 days differentiated cells, but not in animals that received undifferentiated ES transplant. However, the ratio of contralateral to ipsilateral swings in elevated body swing test was significantly reduced in both the transplanted groups, as compared to control. Striatal grafts exhibited the presence of tyrosine hydroxylase positive cells, and the percentage of dopaminergic neurons in the substantia nigra was also found to be higher in the ipsilateral side of 7 days and mES grafted animals. Increased expression of CD11b and IBA-1, suggested a significant contribution of these microglia-derived factors in controlling the limited survival of the grafted cells. Astrocytosis in the grafted striatum, and significant increase in the levels of glial cell line derived neurotrophic factor may have contributed to the recovery observed in the hemiparkinsonian rats following transplantation.
PLoS ONE 09/2013; 8(9):e72501. DOI:10.1371/journal.pone.0072501 · 3.23 Impact Factor
"However, bilateral infusions lead to weight loss and require specialised diets to maintain the animals (Betarbet et al. 2000, Sherer et al. 2003c), possibly due to bilateral lesioning of the ventral tegmental area. These problems are ameliorated by unilateral lesions which reduce dopamine signalling, dopamine level, DOPAC (3,4-dihydroxyphenylacetic acid) level and dopaminergic innervation, while increasing oxidative stress (hydroxyl radicals, GSH level, superoxide dismutase levels), as well as up-regulating α-synuclein expression in the ipsilateral substantia nigra (Sindhu et al. 2006, Antkiewicz-Michaluk et al. 2004, Saravanan, Sindhu and Mohanakumar 2005, Sindhu, Saravanan and Mohanakumar 2005, Ravenstijn et al. 2008, Xiong et al. 2009). Unilateral rotenone lesioned animals have shown differences in several behavioural indices, including rotarod and amphetamine or apomorphine-induced rotation, demonstrating the unilateral functional motor deficits associated with substantia nigra dopamine neuron loss (Sindhu et al. 2006, Sindhu et al. 2005, Ravenstijn et al. 2008, Xiong et al. 2009). "
[Show abstract][Hide abstract] ABSTRACT: Rats with unilateral lesion of the substantia nigra pars compacta (SNpc) have been used as a model of Parkinson's disease. Depending on the lesion protocol and on the drug challenge, these rats rotate in opposite directions. The aim of the present study was to propose a model to explain how critical factors determine the direction of these turns. Unilateral lesion of the SNpc was induced with 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Separate analysis showed that neither the type of neurotoxin nor the site of lesion along the nigrostriatal pathway was able to predict the direction of the turns these rats made after they were challenged with apomorphine. However, the combination of these two factors determined the magnitude of the lesion estimated by tyrosine-hydroxylase immunohistochemistry and HPLC-ED measurement of striatal dopamine. Very small lesions did not cause turns, medium-size lesions caused ipsiversive turns, and large lesions caused contraversive turns. Large-size SNpc lesions resulted in an increased binding of [(3)H]raclopride to D2 receptors, while medium-size lesions reduced the binding of [(3)H]SCH-23390 D1 receptors in the ipsilateral striatum. These results are coherent with the model proposing that after challenged with a dopamine receptor agonist, unilaterally SNpc-lesioned rats rotate toward the side with the weaker activation of dopamine receptors. This activation is weaker on the lesioned side in animals with small SNpc lesions due to the loss of dopamine, but stronger in animals with large lesions due to dopamine receptor supersensitivity.
Behavioural Brain Research 07/2008; 189(2):364-72. DOI:10.1016/j.bbr.2008.01.012 · 3.03 Impact Factor
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