Midkine Is a Novel Regulator of Amphetamine-Induced Striatal Gliosis and Cognitive Impairment: Evidence for a Stimulus-Dependent Regulation of Neuroinflammation by Midkine

Abstract

Midkine (MK) is a cytokine that modulates amphetamine-induced striatal astrogliosis, suggesting a possible role of MK in neuroinflammation induced by amphetamine. To test this hypothesis, we studied astrogliosis and microglial response induced by amphetamine (10 mg/kg i.p. four times, every 2 h) in different brain areas of MK−/− mice and wild type (WT) mice. We found that amphetamine-induced microgliosis and astrocytosis are enhanced in the striatum of MK−/− mice in a region-specific manner. Surprisingly, LPS-induced astrogliosis in the striatum was blocked in MK−/− mice. Since striatal neuroinflammation induced by amphetamine-type stimulants correlates with the cognitive deficits induced by these drugs, we also tested the long-term effects of periadolescent amphetamine treatment (3 mg/kg i.p. daily for 10 days) in a memory task in MK−/− and WT mice. Significant deficits in the Y-maze test were only observed in amphetamine-pretreated MK−/− mice. The data demonstrate for the first time that MK is a novel modulator of neuroinflammation depending on the inflammatory stimulus and the brain area considered. The data indicate that MK limits amphetamine-induced striatal neuroinflammation. In addition, our data demonstrate that periadolescent amphetamine treatment in mice results in transient disruption of learning and memory processes in absence of endogenous MK.

Midkine in the mouse ventral tegmental area limits ethanol intake and Ccl2 gene expression

“…In addition, CCL2 treatment of brain slices containing the substantia nigra increases dopamine neuron firing rates (Guyon et al 2009). Direct infusion of CCL2 into the VTA also increases the amount of phosphorylated TH (Wakida et al 2014), which is an active form of the enzyme. Together, these studies provide evidence that CCL2 regulates dopamine neurotransmission.…”

“…Mdk expression is also induced in the VTA, the nucleus accumbens, and the hippocampus in response to morphine administration (Ezquerra et al , 2007, Garcia-Perez et al , 2015, Garcia-Perez et al , 2014). MDK seems to play an important role in immune responses in the brain in response to amphetamine because Mdk −/− mice show alterations in amphetamine-induced striatal astrocytosis and microgliosis (Vicente-Rodriguez et al , 2016). Thus, targeting MDK and its signaling pathways may be a novel strategy for reducing neuroinflammation and addiction to multiple substances, including alcohol (Vicente-Rodriguez et al , 2016).…”

“…MDK seems to play an important role in immune responses in the brain in response to amphetamine because Mdk −/− mice show alterations in amphetamine-induced striatal astrocytosis and microgliosis (Vicente-Rodriguez et al , 2016). Thus, targeting MDK and its signaling pathways may be a novel strategy for reducing neuroinflammation and addiction to multiple substances, including alcohol (Vicente-Rodriguez et al , 2016). …”

Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation

“…Therefore, MK inhibition using RNA aptamers may provide an effective therapeutic strategy against autoimmune diseases [26]. With regard to the CNS, MK was found to modulate neuroinflammation in both the cortex and the striatum as a result of lipopolysaccharide (LPS) and amphetamine injections [29,30]. However, the role of MK in TBI-induced neuroinflammation is yet to be elucidated.…”

Angiotensin II modulates amphetamine‐induced glial and brain vascular responses, and attention deficit via angiotensin type 1 receptor: Evidence from brain regional sensitivity to amphetamine

“…Within the central nervous system (CNS), astrocytes, microglia and endothelial cells can sense disturbed neuronal activity following injury, disease or neurotoxic agents (Clark et al, ; Shaerzadeh, Streit, Heysieattalab, & Khoshbouei, ). Besides the increase in DA neurotransmission, in brain areas receiving dopaminergic inputs, Amph promotes astrocyte reactivity stimulating cytokine production (Kadota & Kadota, ; Vicente‐Rodriguez et al, ; Du et al, ; Shah, Silverstein, Singh, & Kumar, ). Furthermore, microglial activation has been proposed as a hallmark for Amph derivatives‐induced neurotoxicity (Thomas et al, ), while gene and protein analyses in microglial cells indicate increased cytokine production and nitrosative stress after Amph exposure (Tocharus, Chongthammakun, & Govitrapong, ; Wisor, Schmidt, & Clegern, ).…”