Increased Physiological GDNF Levels Have No Effect on Dopamine Neuron Protection and Restoration in a Proteasome Inhibition Mouse Model of Parkinson’s Disease

Article

作者: Andressoo, Jaan-Olle ; Mätlik, Kärt ; Kopra, Jaakko J ; Garton, Daniel R ; Bhattacharya, Dipabarna ; Piepponen, T Petteri ; Olfat, Soophie ; Iivanainen, Vilma H ; Jakobsson, Johan

Abstract:

Parkinson’s disease (PD) is a progressive neurodegenerative disease that comprises a range of motor and nonmotor symptoms. Glial cell line-derived neurotrophic factor (GDNF) promotes the survival of dopamine neuronsin vitroandin vivo, and intracranial delivery of GDNF has been tested in six clinical trials for treating PD. However, clinical trials with ectopic GDNF have yielded variable results, which could in part result from abnormal expression site and levels caused by ectopic overexpression. Therefore, an important open question is whether an increase in endogenous GDNF expression could be potent in reversing PD progression. Here, we tested the therapeutic potential of endogenous GDNF using mice in which endogenous GDNF can be conditionally upregulated specifically in cells that express GDNF naturally (conditional GDNF hypermorphic mice;GdnfcHyper). We analyzed the impact of endogenous GDNF upregulation in both neuroprotection and neurorestoration procedures, and for both motor and nonmotor symptoms in the proteasome inhibitor lactacystin (LC) model of PD. Our results showed that upregulation of endogenous GDNF in the adult striatum is not protective in LC-induced PD model in mice. Since age is the largest risk factor for PD, we also analyzed the effect of deletion of endogenous GDNF in agedGdnfconditional knock-out mice. We found that GDNF deletion does not increase susceptibility to LC-induced damage. We conclude that endogenous GDNF does not impact the outcome in the LC-induced proteasome inhibition mouse model of Parkinson’s disease.

2019-11-01·Parkinsonism & related disorders3区 · 医学

Systemic LPS-induced neuroinflammation increases the susceptibility for proteasome inhibition-induced degeneration of the nigrostriatal pathway

3区 · 医学

Article

作者: Deneyer, Lauren ; Bentea, Eduard ; Albertini, Giulia ; Massie, Ann

INTRODUCTION:

Besides proteasome dysfunction, neuroinflammation is a common feature in the pathogenesis of Parkinson's disease (PD). Accordingly, peripheral inflammation has been shown to increase the susceptibility of the brain for nigrostriatal degeneration by inducing activation of glial cells and release of pro-inflammatory cytokines in the brain. Given that current animal models of PD fail to recapitulate the pathophysiology occurring in idiopathic PD, the aim of this study was to combine two pathogenic mechanisms (i.e. neuroinflammation and proteasome inhibition) to create a dual-hit mouse model of PD.

METHODS:

We repeatedly injected mice with a low dose of LPS (250 μg/kg/day i. p. for four days) to induce neuroinflammation, followed by a unilateral intranigral injection of lactacystin (LAC; 3 μg). Seven days later, mice were evaluated behaviorally to assess locomotion, anxiety- and depressive-like behavior. Nigrostriatal degeneration was analyzed by measuring striatal dopamine loss as well as loss of nigral dopaminergic neurons. Neuroinflammation was confirmed by quantifying microglial cells in the substantia nigra (SN) and cytokine expression in the striatum.

RESULTS:

Repeated systemic LPS injections increase the number of microglial cells in the SN and induce a mixed profile of pro- and anti-inflammatory cytokines in the striatum without affecting the integrity of the nigrostriatal pathway. Systemic LPS-induced neuroinflammation, however, increases the susceptibility of the nigrostriatal pathway for LAC-induced degeneration.

CONCLUSION:

Recapitulating two relevant etiopathogenic mechanisms of PD - neuroinflammation and proteasome inhibition-, we propose this dual-hit model as a relevant mouse model for PD that could be used to investigate potential therapeutic targets.

2018-01-01·Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova

Signs of anhedonia and destructive changes in the ventral tegmental area of the midbrain in the model of the preclinical Parkinson's disease stage in experiment

Article

作者: Ekimova, I V ; Karpenko, M N ; Gazizova, A R ; Plaksina, D V

Parkinson's disease (PD) is one of incurable socially significant diseases. Success in the PD treatment is associated with the development of the technology of preclinical diagnosis and neuroprotective treatment of the disease. In the experimental model of the preclinical PD stage in rats created by intranasal administration of the proteasome inhibitor lactacystin, signs of depression as an anhedonia symptom were detected for the first time. Anhedonia was combined with the death of about one third of dopamine (DA)-ergic neurons in the ventral tegmental area of the midbrain and their axons in the ventral striatum; and a decrease of dopamine concentration in the ventral striatum (by 40%) and the tyrosine hydroxylase level in surviving DA-ergic neurons. The signs of depression may be an early marker of PD, signaling the onset of neurodegeneration in the mesolimbic brain system and increasing functional deficit of the DA-ergic transmission in the ventral striatum. The study results can be applied to the development of the technology of preclinical PD diagnosis and pathogenetic therapy.

100 项与乳胞素相关的药物交易

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