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PKC and CaMK-II inhibitions coordinately rescue ischemia-induced GABAergic neuron dysfunction.

ABSTRACT: Cerebral ischemia leads to neuronal death for stroke, in which the imbalance between glutamatergic neurons and GABAergic neurons toward neural excitotoxicity is presumably involved. GABAergic neurons are vulnerable to pathological factors and impaired in an early stage of ischemia. The rescue of GABAergic neurons is expected to be the strategy to reserve ischemic neuronal impairment. As protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMK-II) are activated during ischemia, we have investigated whether the inhibitions of these kinases rescue the ischemic impairment of cortical GABAergic neurons. The functions of GABAergic neurons were analyzed by whole-cell recording in the cortical slices during ischemia and in presence of 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperazine (CaMK-II inhibitor) and chelerythrine chloride (PKC inhibitor). Our results indicate that PKC inhibitor or CaMK-II inhibitor partially prevents ischemia-induced functional deficits of cortical GABAergic neurons. Moreover, the combination of PKC and CaMK-II inhibitors synergistically reverses this ischemia-induced deficit of GABAergic neurons. One of potential therapeutic strategies for ischemic stroke may be to rescue the ischemia-induced deficit of cortical GABAergic neurons by inhibiting PKC and CaMK-II.

SUBMITTER: Huang L

PROVIDER: S-EPMC5503615 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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PKC and CaMK-II inhibitions coordinately rescue ischemia-induced GABAergic neuron dysfunction.

Huang Li L Wang Chun C Zhao Shidi S Ge Rongjing R Guan Sudong S Wang Jin-Hui JH

Oncotarget 20170601 24

Cerebral ischemia leads to neuronal death for stroke, in which the imbalance between glutamatergic neurons and GABAergic neurons toward neural excitotoxicity is presumably involved. GABAergic neurons are vulnerable to pathological factors and impaired in an early stage of ischemia. The rescue of GABAergic neurons is expected to be the strategy to reserve ischemic neuronal impairment. As protein kinase C (PKC) and calmodulin-dependent protein kinase II (CaMK-II) are activated during ischemia, we ...[more]

PMID: 28445148

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Project description:Parkinson's disease (PD) is characterized by the presence of ?-synuclein aggregates known as Lewy bodies and Lewy neurites, whose formation is linked to disease development. The causal relation between ?-synuclein aggregates and PD is not well understood. We generated a new transgenic mouse line (MI2) expressing human, aggregation-prone truncated 1-120 ?-synuclein under the control of the tyrosine hydroxylase promoter. MI2 mice exhibit progressive aggregation of ?-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. In the MI2 mice, alterations in gait impairment can be detected by the DigiGait test from 9 months of age, while gross motor deficit was detected by rotarod test at 20 months of age when 50% of dopaminergic neurons in the substantia nigra pars compacta are lost. These changes were associated with an increase in the number and density of 20-500 nm ?-synuclein species as shown by dSTORM. Treatment with the oligomer modulator anle138b, from 9 to 12 months of age, restored striatal dopamine release, prevented dopaminergic cell death and gait impairment. These effects were associated with a reduction of the inner density of large ?-synuclein aggregates and an increase in dispersed small ?-synuclein species as revealed by dSTORM. The MI2 mouse model recapitulates the progressive dopaminergic deficit observed in PD, showing that early synaptic dysfunction is associated to fine behavioral motor alterations, precedes dopaminergic axonal loss and neuronal death that become associated with a more consistent 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 ?-synuclein aggregation is a promising therapeutic approach for PD.

Dataset Information

PKC and CaMK-II inhibitions coordinately rescue ischemia-induced GABAergic neuron dysfunction.

Publications

PKC and CaMK-II inhibitions coordinately rescue ischemia-induced GABAergic neuron dysfunction.

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