Dopamine depletion protects striatal neurons from heatstroke-induced ischemia and cell death in rats

To explore the importance of brain dopamine in the heatstroke-induced striatal ischemia and neuronal injury, we compared the temporal profile of the heatstroke-induced striatal extracellular dopamine release, striatal blood flow, and striatal neuronal loss in rats with or without striatal dopamine depletion produced by 6-hydroxydopamine. In vivo voltammetry was used in rats to measure changes in extracellular concentrations of dopamine in the corpus striatum. Striatal neuronal damage was rated on a scale from zero to three (0, no damage; 3, maximum cell loss). The autoradiographic diffusible tracer technique was used for the measurement of striatal blood flow. After the onset of heatstroke, the heatstroke rats without brain dopamine depletion displayed hyperthermia, decreased mean arterial pressure, increased intracranial pressure, decreased cerebral perfusion pressure, decreased striatal blood flow, increased striatal dopamine release, and increased score of striatal neuronal damage as compared with those of normothermic controls. However, when the striatal dopamine system was destroyed by 6-hydroxydopamine, the heatstroke-induced arterial hypotension, intracranial hypertension, ischemic damage to the striatum, and elevated striatal dopamine release were reduced. In addition, the survival time of the heatstroke rats was prolonged after depleting striatal dopamine. Thus it appears that dopamine depletion protects striatal neurons from heatstroke-induced ischemia and cell death.

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Depopulation of α-synuclein aggregates is associated with rescue of dopamine neuron dysfunction and death in a new Parkinson’s disease model

10.1101/500629 ◽

2018 ◽

Author(s):

Michal Wegrzynowicz ◽

Dana Bar-On ◽

Laura Calo’ ◽

Oleg Anichtchik ◽

Mariangela Iovino ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Dopaminergic Neurons ◽

Dopamine Release ◽

Striatal Dopamine ◽

Substantia Nigra Pars Compacta ◽

Motor Deficit ◽

Promising Therapeutic Approach ◽

Striatal Dopamine Release

SUMMARYParkinson’s Disease (PD) is characterized by the presence of α-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between α-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 α-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of α-synuclein in dopaminergic neurons of the substantia nigra pars compacta and their striatal terminals. This is associated with a progressive reduction of striatal dopamine release, reduced striatal innervation and significant nigral dopaminergic nerve cell death starting from 6 and 12 months of age, respectively. Overt impairment in motor behavior was found in MI2 mice at 20 months of age, when 50% of dopaminergic neurons are lost. These changes were associated with an increase in the number and density of 20-500nm α-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9-12 months of age, restored striatal dopamine release and prevented dopaminergic cell death. These effects were associated with a reduction of the inner density of α-synuclein aggregates and an increase in dispersed small α-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction precedes dopaminergic axonal loss and neuronal death that become associated with a motor deficit upon reaching a certain threshold. Our data also provide new mechanistic insight for the effect of anle138b’s function in vivo supporting that targeting α-synuclein aggregation is a promising therapeutic approach for PD.

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