Abstract
Methylphenidate is a psychostimulant that inhibits the neuronal dopamine transporter. In addition, methylphenidate has the intriguing ability to provide neuroprotection from the neurotoxic effects of methamphetamine and perhaps also Parkinson’s disease; both of which may likely involve the abnormal accumulation of cytoplasmic dopamine inside dopaminergic neurons and the resulting formation of dopamine-associated reactive oxygen species. As delineated in this review, the neuroprotective effects of methylphenidate are due, at least in part, to its ability to attenuate or prevent this abnormal cytoplasmic dopamine accumulation through several possible neuropharmacological mechanisms. These may include 1) direct interactions between methylphenidate and the neuronal dopamine transporter which may attenuate or prevent the entry of methamphetamine into dopaminergic neurons and may also decrease the synthesis of cytoplasmic dopamine through a D2 receptor-mediated signal cascade process, and 2) indirect effects upon the functioning of the vesicular monoamine transporter-2 which may increase vesicular dopamine sequestration through both vesicle trafficking and the kinetic upregulation of the vesicular monoamine transporter-2 protein. Understanding these neuropharmacological mechanisms of methylphenidate neuroprotection may provide important insights into the physiologic regulation of dopaminergic systems as well as the pathophysiology of a variety of disorders involving abnormal dopamine disposition ranging from substance abuse to neurodegenerative diseases such as Parkinson’s disease.
Highlights
Methylphenidate (MPD) is a ritalinic acid psychostimulant as shown in Fig. (1)
MPD alters the transport of dopamine (DA) across the synaptic plasmalemmal membrane by binding with high affinity to, and thereby competitively inhibiting, the neuronal DA transporter (DAT) [20, 48, 49, 75]
MPD can prevent the neurotoxic effects of 1-methyl-4-phenylpyridinium (MPP+) in both human embryonic kidney 293 cells expressing the human DAT and in rat embryonic mesencephalic cultures by blocking the DAT [30]. In order for this proposed neuropharmacological mechanism of MPD neuroprotection to be valid, METH must be transported by the DAT and not diffuse passively across the plasmalemmal membrane
Summary
Methylphenidate (MPD) is a ritalinic acid psychostimulant as shown in Fig. (1). It was first synthesized in 1944 [40] and is sold under several brand names including Ritalin and Concerta. These neuroprotective effects of MPD may be due, at least in part, to its ability to attenuate or prevent abnormal cytoplasmic DA accumulation in dopaminergic neurons by modulating the activity of the DAT and the VMAT-2 through several neuropharmacological mechanisms. Through these direct binding interactions with the DAT, MPD may exert its neuroprotective effects through at least two possible neuropharmacological mechanisms.
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