Chronic MPTP treatment produces hyperactivity in male mice which is not alleviated by concurrent trehalose treatment

Ferguson, Sherry A.; Law, C. Delbert; Sarkar, Sumit

doi:10.1016/j.bbr.2015.05.057

Cited by 20 publications

(10 citation statements)

References 47 publications

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“…Furthermore, trehalose did not alter levels of striatal aSyn. These results are in contrast to previous studies, which demonstrated that trehalose can protect TH 1ve cells in the SN (Sarkar et al, 2014;Ferguson et al, 2015;He et al, 2016) and reduce striatal aSyn (He et al, 2016). Some of these observed differences are likely due to differences in the animal model used, e.g., AAV1/2-hourA53T-aSyn versus MPTP mouse.…”

Section: Discussioncontrasting

confidence: 96%

“…Thus, administration of trehalose ad libitum in drinking water (2% w/v) has been shown, in MPTP-lesioned mice, to prevent loss of DAT and TH staining in the striatum and SN, and to prevent dopamine loss in the striatum (Sarkar et al, 2014). Similar results were obtained in the same model by Ferguson et al, (2015) when a lower dose of trehalose (1% w/v in drinking water) was used, with significant prevention of dopamine loss and the number of TH 1ve cells in the SN, although in that study trehalose did not alter MPTP-induced behavioral abnormalities.…”

Section: Discussionsupporting

confidence: 62%

“…Trehalose, a disaccharide formed by an a,a-1,1-glucoside bond between two a-glucose molecules is beneficial in various animal models of neurodegeneration (for a recent review, see Hosseinpour-Moghaddam et al, 2018). In animal models of PD, trehalose has demonstrated efficacy in toxin-induced lesion models (Sarkar et al, 2014;Ferguson et al, 2015;Wu et al, 2015), in models overexpressing mutant aSyn by viral vectors (He et al, 2016), and by transgenesis (Tanji et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

Howson¹,

Johnston²,

Ravenscroft³

et al. 2019

J Pharmacol Exp Ther

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Disease modification in Parkinson's disease (PD) is an unmet medical need. In the current study, we evaluated trehalose, a safe and well-tolerated disaccharide that has previously demonstrated efficacy in rodent models of neurodegenerative diseases, including PD. In a rat model of PD, based on delivery of adeno-associated virus serotype 1/2 containing the mutated human A53T a-synuclein gene (AAV1/2-hourA53T-aSyn) to the substantia nigra (SN), we showed that rats administered trehalose (2.67 g/kg per day, by mouth) for 6 weeks had less forelimb asymmetry (93% reduction) and higher striatal dopamine (54% increase) compared with rats receiving vehicle. In a pharmacokinetic study, we determined that efficacy was associated with plasma C max of 8900 ng/ml and area under the curve from time 0 to infinity (AUC 0-inf) of 11,136 hour×ng/ml. We then showed, in macaques, that oral administration of trehalose (2.67 g/kg per day) produced plasma exposures of similar magnitude, with plasma C max of 10,918 ng/ml and AUC 0-inf of 27,445 hour×ng/ml. In a macaque model of PD, also based on delivery of AAV1/2-hourA53T-aSyn to the SN, trehalose (2.67 g/kg per day, by mouth), administered for 142 days, produced higher striatal dopamine (by 39%) and dopamine transporter levels (by 50%), compared with macaques receiving vehicle. In neither model did trehalose treatment prevent loss of tyrosine hydroxylase (TH) positive (TH 1ve) cells in the SN or alter a-synuclein levels in the striatum. These studies demonstrated that trehalose reduces striatal dopaminergic deficits in a rodent and macaque model of synucleinopathy in PD. Furthermore, we have determined the pharmacokinetic parameters associated with efficacy, and thus defined exposures to target in future clinical trials.

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Section: Discussioncontrasting

confidence: 96%

Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

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Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

Howson¹,

Johnston²,

Ravenscroft³

et al. 2019

J Pharmacol Exp Ther

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“…This resulted in a heightened number and distance covered by forepaw movements relative to controls. It is suggestive of hyperactivity and therefore in agreement with findings obtained in MPTP mice in the open field2728, but appears to be dependent on the method of detection20. Moreover, the occurrence of Steps with Touches, an otherwise rare event in normal controls, is of significance for both the MPTP model as it reflects a deficit in motor planning, and the TracMouse script enables for the first time to detect such a parameter.…”

Section: Discussionsupporting

confidence: 82%

TracMouse: A computer aided movement analysis script for the mouse inverted horizontal grid test

Niewiadomski

Pałasz²,

Skupinska³

et al. 2016

Sci Rep

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In rodents, detection and quantification of motor impairments is difficult. The traction test (inverted grid with mice clinging to the underside) currently has no objective rating system. We here developed and validated the semi-automatic MATLAB script TracMouse for unbiased detection of video-recorded movement patterns. High precision videos were analyzed by: (i) principal identification of anatomical paw details frame-by-frame by an experimentally blinded rater; (ii) automatic retrieval of proxies by TracMouse for individual paws. The basic states of Hold and Step were discriminated as duration and frequency, and these principle parameters were converted into static and dynamic endpoints and their discriminating power assessed in a dopaminergic lesion model. Relative to hind paws, forepaws performed ~4 times more steps, they were ~20% longer, and Hold duration was ~5 times shorter in normal C57Bl/6 mice. Thus, forepaw steps were classified as exploratory, hind paw movement as locomotive. Multiple novel features pertaining to paw sequence, step lengths and exploratory touches were accessible through TracMouse and revealed subtle Parkinsonian phenotypes. Novel proxies using TracMouse revealed previously unidentified features of movement and may aid the understanding of (i) brain circuits related to motor planning and execution, and (ii) phenotype detection in experimental models of movement disorders.

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“…In this study, the mice were able to perform the physical exercise without any noticeable problems, suggesting that their physical exercise regimen is comparable to the forced moderate aerobic exercise that has been shown to improve both motor and non-motor functions in PD patients [ 11 , 60 , 63 , 64 ]. MPTP treatment alone resulted in an increased activity in the open field, as reported before [ 48 , 52 , 65 – 67 ], but did not affect the performance on beam walk and rotarod. It should be noted that the training effect on the beam walk as seen in all four treatment groups, especially in week 1 compared to week 0, may implicate the necessity for more extensive training of the mice before the beam walk task in week 0.…”

Section: Discussionsupporting

confidence: 78%

Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson’s Disease

et al. 2017

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Parkinson’s disease (PD) is characterized by the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc), resulting in motor and non-motor dysfunction. Physical exercise improves these symptoms in PD patients. To explore the molecular mechanisms underlying the beneficial effects of physical exercise, we exposed 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrimidine (MPTP)-treated mice to a four-week physical exercise regimen, and subsequently explored their motor performance and the transcriptome of multiple PD-linked brain areas. MPTP reduced the number of DA neurons in the SNpc, whereas physical exercise improved beam walking, rotarod performance, and motor behavior in the open field. Further, enrichment analyses of the RNA-sequencing data revealed that in the MPTP-treated mice physical exercise predominantly modulated signaling cascades that are regulated by the top upstream regulators L-DOPA, RICTOR, CREB1, or bicuculline/dalfampridine, associated with movement disorders, mitochondrial dysfunction, and epilepsy-related processes. To elucidate the molecular pathways underlying these cascades, we integrated the proteins encoded by the exercise-induced differentially expressed mRNAs for each of the upstream regulators into a molecular landscape, for multiple key brain areas. Most notable was the opposite effect of physical exercise compared to previously reported effects of L-DOPA on the expression of mRNAs in the SN and the ventromedial striatum that are involved in—among other processes—circadian rhythm and signaling involving DA, neuropeptides, and endocannabinoids. Altogether, our findings suggest that physical exercise can improve motor function in PD and may, at the same time, counteract L-DOPA-mediated molecular mechanisms. Further, we hypothesize that physical exercise has the potential to improve non-motor symptoms of PD, some of which may be the result of (chronic) L-DOPA use.Electronic supplementary materialThe online version of this article (10.1007/s12035-017-0775-0) contains supplementary material, which is available to authorized users.

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Chronic MPTP treatment produces hyperactivity in male mice which is not alleviated by concurrent trehalose treatment

Cited by 20 publications

References 47 publications

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

TracMouse: A computer aided movement analysis script for the mouse inverted horizontal grid test

Physical Exercise Modulates L-DOPA-Regulated Molecular Pathways in the MPTP Mouse Model of Parkinson’s Disease

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