Dual effects of l-DOPA on nigral dopaminergic neurons

Guatteo, Ezia; Yee, Andrew G.; McKearney, James W.; Cucchiaroni, Maria Letizia; Armogida, Marta; Berretta, Nicola; Mercuri, Nicola Biagio; Lipski, Janusz

doi:10.1016/j.expneurol.2013.02.009

Cited by 40 publications

(33 citation statements)

References 77 publications

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“…We interpret this pharmacological effect as reflecting the motor impairment caused by excess dopamine and altered dopamine signaling in the striatum (Chesselet et al, 2012; Fleming et al, 2006; Fredriksson et al, 1990; Oksman et al, 2009) since these young Thy1-aSyn mice have excess extracellular dopamine in the striatum and altered striatal synaptic response to dopamine agonists and antagonists, pointing towards alteration of D2 receptor modulation (Lam et al, 2011). A similar effect on errors per step in Thy1-aSyn mice was produced by TRO40303, which increased the level of several transcripts involved in dopamine synthesis, suggesting that it may further increase dopamine level to impair motor performance on the beam similarly to l-dopa and apomorphine, perhaps through a mechanism involving D2 autoreceptors (Beaulieu and Gainetdinov, 2011; Guatteo et al, 2013; Muller et al, 2004). …”

Section: Resultsmentioning

confidence: 84%

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Richter¹,

Gao²,

Medvedeva³

et al. 2014

Neurobiology of Disease

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Cholesterol-oximes TRO19622 and TRO40303 target outer mitochondrial membrane proteins and have beneficial effects in preclinical models of neurodegenerative diseases leading to their advancement to clinical trials. Dopaminergic neurons degenerate in Parkinson’s disease (PD) and are prone to oxidative stress and mitochondrial dysfunction. In order to provide insights into the neuroprotective potential of TRO19622 and TRO40303 for dopaminergic neurons in vivo, we assessed their effects on gene expression in laser captured nigrostriatal dopaminergic neurons of wildtype mice and of mice that over-express alpha-synuclein, a protein involved in both familial and sporadic forms of PD (Thy1-aSyn mice). Young mice were fed the drugs in food pellets or a control diet from 1 to 4 months of age, approximately 10 months before the appearance of striatal dopamine loss in this model. Unbiased weighted gene co-expression network analysis (WGCNA) of transcriptional changes revealed effects of cholesterol oximes on transcripts related to mitochondria, cytoprotection and anti-oxidant response in wild-type and transgenic mice, including increased transcription of stress defense (e.g. Prdx1, Prdx2, Glrx2, Hspa9, Pink1, Drp1, Trak1) and dopamine-related (Th, Ddc, Gch1, Dat, Vmat2, Drd2, Chnr6a) genes. Even at this young age transgenic mice showed alterations in transcripts implicated in mitochondrial function and oxidative stress (e.g. Bcl-2, Bax, Casp3, Nos2), and both drugs normalized about 20% of these alterations. Young Thy1-aSyn mice exhibit motor deficits that differ from parkinsonism and are established before the onset of treatment; these deficits were not improved by cholesterol oximes. However, high doses of TRO40303 improved olfaction and produced the same effects as dopamine agonists on a challenging beam test, specifically an increase in footslips, an observation congruent with its effects on transcripts involved in dopamine synthesis. High doses of TRO19622 increased alpha-synuclein aggregates in the substantia nigra; this effect, not seen with TRO40303 was inconsistent and may represent a protective mechanism as in other neurodegenerative diseases. Overall, the results suggest that cholesterol oximes, while not improving early effects of alpha-synuclein overexpression on motor behavior or pathology, may ameliorate the function and resilience of dopaminergic neurons in vivo and support further studies of neuroprotection in models with dopaminergic cell loss.

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Section: Resultsmentioning

confidence: 84%

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Richter¹,

Gao²,

Medvedeva³

et al. 2014

Neurobiology of Disease

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“…We ruled out this possibility with a series of control experiments on theoretical candidates of excitatory side effects of dopamine exposure. In particular, we focused our attention on a possible cross‐stimulation on adrenoceptors (Cornil et al ., ; Swaminath et al ., ; Zhang et al ., ; Cucchiaroni et al ., ) or α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) glutamate receptors (Guatteo et al ., ).…”

Section: Resultsmentioning

confidence: 97%

Reversal of dopamine‐mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons

Aversa

Martini

Guatteo

et al. 2018

British J Pharmacology

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“…Using a combination of electrophysiology and calcium microfluorometry in brain slices, Guatteo et al [52] demonstrated that L-DOPA has dual, inhibitory and excitatory, effects on nigral dopaminergic neurons, and suggested that the excitation and calcium rise may have long-lasting consequences for the activity and survival of these neurons when the expression or function of D2 receptors is impaired.…”

Section: Discussionmentioning

confidence: 99%

Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson’s Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

Araújo

Sousa

Araújo

et al. 2013

Evidence-Based Complementary and Alternative Medicine

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This study aimed to investigate behavioral and neurochemical effects of α-lipoic acid (100 mg/kg or 200 mg/kg) alone or associated with L-DOPA using an animal model of Parkinson's disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. α-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA) at cylinder test. α-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, α-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that α-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment.

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Dual effects of l-DOPA on nigral dopaminergic neurons

Cited by 40 publications

References 77 publications

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Chronic administration of cholesterol oximes in mice increases transcription of cytoprotective genes and improves transcriptome alterations induced by alpha-synuclein overexpression in nigrostriatal dopaminergic neurons

Reversal of dopamine‐mediated firing inhibition through activation of the dopamine transporter in substantia nigra pars compacta neurons

Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson’s Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat

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