Early stages of Parkinson’s disease: comparative characteristics of sleep–wakefulness cycle in patients and model animals

Kovalzon, V. M.; Ugrumov, M. V.; Pronina, T. S.; Vb, Dorokhov; Manolov, Alexander I.; Долгих, В. В.; Ukraintseva, Yu. V.; Moiseenko, L. S.; Полуэктов, М Г; Калинкин, А. Л.

doi:10.1134/s0362119715040106

Cited by 7 publications

(5 citation statements)

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“…In present experiments as well as the cited publication, mice demonstrated increased motor activity, elongated total wake time, and shortened NREM and REM sleep time during the darkness (period of diurnal activity) within two weeks after systemic MPTP administration. These changes are observed in the same circadian period of pineal melatonin production when the corresponding sleep disorders are observed in Parkinson’s disease patients [ 24 ]. The transplantation of cells with transgenic GDNF lacking the pre- and pro-regions into the striatum 3 days prior to MPTP administration efficiently antagonized these changes.…”

Section: Discussionmentioning

confidence: 92%

“…In particular, many patients demonstrate prolonged nighttime awakenings and reduced NREM and REM sleep [ 21 , 22 ]. In the MPTP model of early Parkinson’s disease, experimental mice also demonstrate increased activity and reduced NREM and REM sleep at nighttime [ 23 ], i.e., in the same period of pineal melatonin production when the corresponding sleep disorders are observed in patients [ 24 ]. So, this model is adequate for studying the effects of various biochemical factors in early Parkinson’s disease.…”

Section: Introductionmentioning

confidence: 99%

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Effects of striatal transplantation of cells transfected with GDNF gene without pre- and pro-regions in mouse model of Parkinson’s disease

et al. 2016

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BackgroundPreviously, we have shown that transgenic cells bearing the GDNF gene with deleted pre- and pro-regions (mGDNF) can release transgenic GDNF. The medium conditioned by transgenic cells with mGDNF induced axonal growth in rat embryonic spinal ganglion in vitro. Here we demonstrate a neurotrophic effect of mGDNF on PC12 cells in vitro as well as its neuroprotective effect on dopaminergic neurons in the substantia nigra pars compacta in vivo as indicated by improved motor coordination and sleep-wakefulness cycle in the MPTP mouse model of Parkinson’s disease.ResultsHEK293 cells were transfected with a vector encoding an isoform of the human GDNF gene with deleted pre- and pro-regions (mGDNF). This factor in the medium conditioned by the transfected cells was shown to induce axonal growth in PC12 cells. The early Parkinson’s disease model was established by injection of the dopaminergic pro-neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) into C57Bl/6 mice. Transgenic HEK293/mGDNF/GFP cells were transplanted into the striatum (caudate-putamen) of experimental mice. The sleep-wakefulness cycle was studied by continuous EEG and motor activity monitoring 1 and 2 weeks after MPTP injection. After the experiment, the motor coordination of experimental animals was evaluated in the rotarod test, and dopaminergic neurons in the substantia nigra pars compacta were counted in cross-sections of the midbrain. MPTP administration lowered the number of tyrosine hydroxylase immunopositive cells in the substantia nigra pars compacta, decreased motor coordination, and increased the total wake time during the dark period. The transplantation of HEK293/mGDNF cells into the caudate-putamen 3 days prior to MPTP injection smoothed these effects, while the control transplantation of HEK293 cells showed no notable impact.ConclusionsTransplantation of transgenic cells with the GDNF gene lacking the pre- and pro-sequences can protect dopaminergic neurons in the mouse midbrain from the subsequent administration of the pro-neurotoxin MPTP, which is confirmed by polysomnographic, behavioral and histochemical data. Hence it is released from transfected cells and preserves the differentiation activity and neuroprotective properties.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Effects of striatal transplantation of cells transfected with GDNF gene without pre- and pro-regions in mouse model of Parkinson’s disease

et al. 2016

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“…Here, we aimed to assess the role of CDK5 in the regulation of circadian rest/activity behavior using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to generate dorsal striatum (DS)-specific CDK5 knockdown (KD) mice (referred to as DS-CDK5-KD mice). The DS was selected because it is a major area of DA involvement in the early stages of motor processing, and DS disturbance may produce the well-documented behavioral changes associated with cerebral neurodegenerative disorders [ 26 ]. In addition to assessing motor activity, we examined the changes of wake/sleep behaviors in DS-CDK5-KD mice.…”

Section: Introductionmentioning

confidence: 99%

Downregulation of CDK5 signaling in the dorsal striatum alters striatal microcircuits implicating the association of pathologies with circadian behavior in mice

Zhou¹,

Zhang²,

Shi³

et al. 2022

Mol Brain

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Dysfunction of striatal dopaminergic circuits has been implicated in motor impairment and Parkinson’s disease (PD)-related circadian perturbations that may represent an early prodromal marker of PD. Cyclin-dependent kinase 5 (CDK5) negatively regulates dopamine signaling in the striatum, suggesting a critical role of CDK5 in circadian and sleep disorders. Here, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to produce mice with a dorsal striatum (DS)-specific knockdown (KD) of the Cdk5 gene (referred to as DS-CDK5-KD mice) and investigate its role in vivo. DS-CDK5-KD mice exhibited deficits in locomotor activity and disturbances in activity/rest behavior. Additionally, Golgi staining of neurons in the DS revealed that CDK5 deletion reduced dendrite length and the number of functional synapses, which was confirmed by significant downregulation of MAP2, PSD-95, and synapsin I. Correlated with this, DS-CDK5-KD mice displayed reduced phosphorylation of Tau at Thr181. Furthermore, whole-cell patch-clamp recordings of green fluorescent protein-tagged neurons in the striatum of DS-CDK5-KD mice revealed a decreased frequency of spontaneous inhibitory postsynaptic currents and altered excitatory/inhibitory synaptic balance. Notably, anterograde labeling showed that CDK5 KD in the DS disrupted long-range projections to the secondary motor cortex, dorsal and ventral thalamic nuclei, and basolateral amygdala, which are involved in the regulation of motor and circadian rhythms in the brain. These findings support a critical role of CDK5 in the DS in maintaining the striatal neural circuitry underlying motor functions and activity/rest associated with circadian rhythms that are perturbed in neurodegenerative disorders.

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“…Of course, neuroprotective treatment can be effective only if it is started at an early stage, not later, when most of the neurons have already died [3,[7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Preventive Activity of the Extract of the Darkling Beetle <em>Ulomoides Dermestoides</em> in the Diet of C57Bl/6JSTO Mice in a Neurotoxic Model of Parkinson's Disease

Kovalzon¹,

Ambaryan²,

Revishchin³

et al. 2021

Preprint

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The effect of aqueous extracts of the biomass of the adult Ulomoides dermestoides beetle on the delayed effects of the defoliant paraquat causing parkinsonism in experimental mice was evaluated. The motor activity of the animals was analyzed in behavioral tests using a rotarod and a vertical pole. The number of tyrosine hydroxylase-immunopositive neurons in the ventral part of the substantia nigra of the midbrains of experimental and control mice was studied by immunohistochemistry. In the model in vitro system with SH-SY5Y human neuroblastoma, the effect of the extracts on cell proliferation was examined in the absence and presence of the neurotoxin MPP+. The isolation of biologically active substances from raw biomass using cavitation effects made it possible to obtain extracts with protective properties in the model of an early stage of Parkinson's disease used in this study.

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Early stages of Parkinson’s disease: comparative characteristics of sleep–wakefulness cycle in patients and model animals

Cited by 7 publications

References 10 publications

Effects of striatal transplantation of cells transfected with GDNF gene without pre- and pro-regions in mouse model of Parkinson’s disease

Effects of striatal transplantation of cells transfected with GDNF gene without pre- and pro-regions in mouse model of Parkinson’s disease

Downregulation of CDK5 signaling in the dorsal striatum alters striatal microcircuits implicating the association of pathologies with circadian behavior in mice

Preventive Activity of the Extract of the Darkling Beetle <em>Ulomoides Dermestoides</em> in the Diet of C57Bl/6JSTO Mice in a Neurotoxic Model of Parkinson's Disease

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