Vesicular monoamine transporter 2: Role as a novel target for drug development

Zheng, Guangrong; Dwoskin, Linda P.; Crooks, Peter A.

doi:10.1208/aapsj080478

Cited by 109 publications

(78 citation statements)

References 111 publications

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“…This finding indicates that the intracellular decarboxylation process in RIN-5mF cells was not considerably affected by the pharmacologic inhibition by carbidopa. The upregulation of AADC activity in NET cells supports this finding (10,17).…”

Section: Discussionsupporting

confidence: 70%

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Effect of Carbidopa on ¹⁸F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging

Détour¹,

Aimar²,

Boisson³

et al. 2016

J Nucl Med

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Patient premedication with carbidopa seems to improve the accuracy of 6-18 F-fluoro-3,4-dihydroxy-L-phenylalanine ( 18 F-FDOPA) PET for insulinoma diagnosis. However, the risk of PET false-negative results in the presence of carbidopa is a concern. Consequently, we aimed to evaluate the effect of carbidopa on 18 F-FDOPA uptake in insulinoma b-cells and an insulinoma xenograft model in mice. Methods: 18 F-FDOPA in vitro accumulation was assessed in the murine b-cell line RIN-m5F. In vivo small-animal PET experiments were performed on tumor-bearing nude mice after subcutaneous injection of RIN-m5F cells. Experiments were conducted with and without carbidopa pretreatment. Results: Incubation of RIN-m5F cells with 80 mM carbidopa did not significantly affect the cellular accumulation of 18 F-FDOPA. Tumor xenografts were clearly detectable by small-animal PET in all cases. Insulinoma xenografts in carbidopa-treated mice showed significantly higher 18 F-FDOPA uptake than those in nontreated mice. Regardless of carbidopa premedication, the xenografts were characterized by an early increase in 18 F-FDOPA uptake and then a progressive reduction over time. Conclusion: Carbidopa did not influence in vitro 18 F-FDOPA accumulation in RIN-m5F cells but improved insulinoma imaging in vivo. Our findings increase current knowledge about the 18 F-FDOPA uptake profile of RIN-m5F cells and a related xenograft model. To our knowledge, the present work represents the first preclinical research specifically focused on insulinomas, with potential translational implications.

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Section: Discussionsupporting

confidence: 70%

“…In a similar experiment with RPMI culture medium, cells were incubated separately with 10 mM 2-aminobicyclo[2.2.1]heptane-2-carboxylic acid (BCH), described as an L-amino acid transporter inhibitor (16), and 10 mM tetrabenazine, described as an inhibitor of the vesicular monoamine transporter (17).…”

Section: In Vitro Determination Of 18 F-fdopa Accumulationmentioning

confidence: 99%

Effect of Carbidopa on ¹⁸F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging

Détour¹,

Aimar²,

Boisson³

et al. 2016

J Nucl Med

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“…Our data support the notion that dysregulated intracellular dopamine homeostasis could be a central pathogenic event making dopaminergic neurons selectively vulnerable in PD. This hypothesis is already gaining significant attention as substantial progress has been made in evaluating the potential pharmacological modulation of VMAT2 as a therapeutic, disease modifying target for PD (reviewed by Zheng et al, 2006). Furthermore, human data support a neuroprotective role of VMAT2.…”

Section: Discussionmentioning

confidence: 99%

Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels

Vergo¹,

Johansen²,

Leist³

et al. 2007

Brain Research

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A B S T R A C TAn abnormal accumulation of cytosolic dopamine resulting in reactive oxygen species and dopamine-quinone products may play an important role in the rather selective degeneration of substantia nigra pars compacta (SNc) dopaminergic neurons in Parkinson's disease. The neuronal-specific vesicular monoamine transporter (VMAT2), responsible for uptake of dopamine into vesicles, has been shown to play a central role both in intracellular dopamine homeostasis and sequestration of dopaminergic neurotoxins. Direct or indirect enhancement of VMAT2 activity could therefore have neuroprotective effects by decreasing cytosolic dopamine levels. Here, we demonstrate that transfection of VMAT2 in the dopaminergic cell line, PC12, increases intracellular dopamine content, augments potassium-induced dopamine release and attenuates cell death induced by the cytosolic dopamine enhancer, methamphetamine, suggesting an enhancement in vesicular dopamine storage. In rat ventral mesencephalic cultures highly enriched for dopaminergic neurons, lentiviral delivery of recombinant VMAT2 using a neuronal-specific promoter also resulted in elevated intracellular dopamine content and neurotransmitter release after depolarization. The opposite was seen after downregulation of VMAT2 using virally delivered shRNAs. Furthermore, using this VMAT2 knockdown model, we are the first to report a direct link between enhanced cytoplasmic dopamine levels, measured following mild permeabilization of the plasma membrane using digitonin, and neurite degeneration in primary dopaminergic neurons. In conclusion, our data support the hypothesis that an increase in vesicular sequestration of dopamine by modulation of VMAT2 activity could restore neuronal function and enhance dopaminergic cell survival in conditions of dysregulated dopamine homeostasis such as Parkinson's disease.

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“…VMAT2 is a VMAT subtype and the only transporter that transports dopamine into the synapse for storage and release. Once synthesized in the neurons of the pars compacta of the substantia nigra, dopamine is taken up from the synaptic gap by the dopamine transporter, transported into small vesicles for storage by VMAT2 on the synaptic vesicle membranes, and then released into the synaptic gap for recycling (Zheng et al 2006). VMAT2 removes toxins that enter vesicles via the dopamine transporter to reduce the damage to dopaminergic neurons (Miller et al 1999a) and takes up monoamine neurotransmitters into synaptic vesicles to reduce the toxicity caused by free radicals produced by the oxidation of monoamine neurotransmitters (Liu et al 1992).…”

Section: Discussionmentioning

confidence: 99%

Metabolic Changes Induced by Bushenhuoxue Granules on Striatum and Substantia Nigra in a Rat Model of Parkinson’s Disease

Guo¹,

Zhang²,

Li³

et al. 2017

AJTCAM

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Background: Parkinson's disease is a neurodegenerative disease, while its mechanism is still unclear. Long-term levodopa-based treatment leads to decreased response or loss of response, as well as severe side effects. Our previous study has proved that Bushenhuoxue Granules have effects on Parkinson's disease, but the underlying mechanism is still need to be explored. Our research is to investigate the mechanisms of Bushenhuoxue Granules on Parkinson's disease (PD) by examining changes in the expression of the adenosine A 2A receptor、 vesicular monoamine transporter 2 (VMAT2)、 divalent metal transporter 1（DMT1） and nuclear factor E2 related (Nrf2) in a rat model of Parkinson's disease (PD) . Materials and Methods: Changes in the apomorphine (APO)-induced rotational behavior of rats were observed after treatment. Immunofluorescence and immunohistochemistry were performed to investigate changes in adenosine A 2A receptor 、VMAT2、DMT1 and Nrf2 expression in the rat striatum and substantia nigra. Results: Rotations after treatment were199.11 ± 27.16, which significantly decreased compared with that before treatment ( 273.0 ± 44.61, p < 0.01). Adenosine A 2A receptor expression in the striatum was 3.10 ± 0.34 significantly increased in the model group and decreased in the normal control group, whereas the expression level in the Bushenhuoxue group was 1.13 ± 0.23,p < 0.05 between the two control groups. No adenosine A 2A receptor expression was observed in the substantia nigra. VMAT2 expression in the rat striatum was 23.20 ± 2.68 and substantia nigra was 15.98 ± 0.70 increased in the normal control group. They were 8.99 ± 0.48 in the rat striatum and 8.45 ± 0.59 substantia nigra significantly decreased in the model control group, whereas the expression level in the Bushenhuoxue group was 15.36 ± 0.89 in the rat striatum and 11.69 ± 1.17 in the rat substantia nigra (p < 0.05), also between the two control groups. DMT1 expression in the rat striatum was 3.30 ± 0.30 and substantia nigra was 6.56 ± 0.64 decreased in the normal control group. They were 7.92 ± 0.52 in the rat striatum and 12.76 ± 0.86 substantia nigra significantly increased in the model control group, whereas the expression level in the Bushenhuoxue group was 6.17 ± 0.27 in the rat striatum and 9.13 ± 0.44 in the rat substantia nigra (p < 0.05), also between the two control groups. Nrf2 expression in the rat striatum was 7.90 ± 0.29 and substantia nigra was 15.22 ± 1.22 increased in the normal control group. They were 3.09 ± 0.43 in the rat striatum and 8.57 ± 0.54 substantia nigra significantly decreased in the model control group, whereas the expression level in the Bushenhuoxue group was 5.00 ± 0.34 in the rat striatum and 12.46 ± 0.62 in the rat substantia nigra (p< 0.05), also between the two control groups. Conclusion: Bushenhuoxue Granules significantly improved the rotational behavior of PD's rats, decreased adenosine A 2A receptor expression, and increased VMAT2 expression; decreased DMT1 expression, and increased Nfr2 expression.

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Vesicular monoamine transporter 2: Role as a novel target for drug development

Cited by 109 publications

References 111 publications

Effect of Carbidopa on ¹⁸F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging

Effect of Carbidopa on ¹⁸F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging

Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels

Metabolic Changes Induced by Bushenhuoxue Granules on Striatum and Substantia Nigra in a Rat Model of Parkinson’s Disease

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Vesicular monoamine transporter 2: Role as a novel target for drug development

Cited by 109 publications

References 111 publications

Effect of Carbidopa on 18F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging

Effect of Carbidopa on 18F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging

Vesicular monoamine transporter 2 regulates the sensitivity of rat dopaminergic neurons to disturbed cytosolic dopamine levels

Metabolic Changes Induced by Bushenhuoxue Granules on Striatum and Substantia Nigra in a Rat Model of Parkinson’s Disease

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Effect of Carbidopa on ¹⁸F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging

Effect of Carbidopa on ¹⁸F-FDOPA Uptake in Insulinoma: From Cell Culture to Small-Animal PET Imaging