Neuropharmacological Mechanisms Underlying the Neuroprotective Effects of Methylphenidate

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.

Oxidative Stress and ADHD

“…Although dopamine and other catecholamines possess antioxidative and free radical scavenging properties (Cao, Sofic, & Prior, 1997; Yen & Hsieh, 1997), dopamine is easily oxidized and generates highly reactive metabolites such as dopamine quinone, which further lead to mitochondrial dysfunction and oxidative stress (Miyazaki & Asanuma, 2008). Thus, it is not surprising to see the “paradoxical effect” of stimulant treatment, which causes oxidative stress (El-Tawil, Abou-Hadeed, El-Bab, & Shalaby, 2011; Martins et al, 2006) but is also neuroprotective (Volz, 2008) and is an effective treatment for ADHD (Faraone & Buitelaar, 2010). In contrast, clonidine, which is also an effective treatment for ADHD, reduces oxidative stress in rats (Filos et al, 2012; Nik Yusoff, Mustapha, Govindasamy, & Sirajudeen, 2013).…”

Acute administration of methylphenidate alters the prefrontal cortex neuronal activity in a dose–response characteristic

“…38 Moreover α 2A adrenoreceptors could be responsible for the inhibitory response observed at low doses, as ob served in selective α 2A -antagonist studies in which MPD activity was suppressed. 39 The PFC cytoarchitecture is highly heterogeneous; the pyramidal neurons contain DA, NE, and glutamate receptors.…”

Effects of Long-Acting Methylphenidate in Adults with Attention Deficit Hyperactivity Disorder: A Study with Paired-Pulse Transcranial Magnetic Stimulation

“…In addition, Mph binds to and inhibits the neuronal norepinephrine transporter [31] . More neuronal transporters and receptors are affected, since Mph also binds to muscarinic and serotonergic receptors and to serotonin transporters in the brain [32] .…”