Striatal Astrocytes Act as a Reservoir for L-DOPA

Abstract

L-DOPA is therapeutically efficacious in patients with Parkinson’s disease (PD), although dopamine (DA) neurons are severely degenerated. Since cortical astrocytes express neutral amino acid transporter (LAT) and DA transporter (DAT), the uptake and metabolism of L-DOPA and DA in striatal astrocytes may influence their availability in the dopaminergic system of PD. To assess possible L-DOPA- and DA-uptake and metabolic properties of striatal astrocytes, we examined the expression of L-DOPA, DA and DAT in striatal astrocytes of hemi-parkinsonian model rats after repeated L-DOPA administration, and measured the contents of L-DOPA, DA and their metabolite in primary cultured striatal astrocytes after L-DOPA/DA treatment. Repeated injections of L-DOPA induced apparent L-DOPA- and DA-immunoreactivities and marked expression of DAT in reactive astrocytes on the lesioned side of the striatum in hemi-parkinsonian rats. Exposure to DA for 4h significantly increased the levels of DA and its metabolite DOPAC in cultured striatal astrocytes. L-DOPA was also markedly increased in cultured striatal astrocytes after 4-h L-DOPA exposure, but DA was not detected 4 or 8h after L-DOPA treatment, despite the expression of aromatic amino acid decarboxylase in astrocytes. Furthermore, the intracellular level of L-DOPA in cultured striatal astrocytes decreased rapidly after removal of extracellular L-DOPA. The results suggest that DA uptaken into striatal astrocytes is rapidly metabolized and that striatal astrocytes act as a reservoir of L-DOPA that govern the uptake or release of L-DOPA depending on extracellular L-DOPA concentration, but are less capable of converting L-DOPA to DA.

Intermittent theta‐burst stimulation rescues dopamine‐dependent corticostriatal synaptic plasticity and motor behavior in experimental parkinsonism: Possible role of glial activity

“…Also the finding of astrocytic changes in shape and functions in association with DA levels is supported by studies demonstrating that these cells in critical conditions release DA and express enzymes and the complete machinery to metabolize it . Moreover, relevant to PD, astrocytes can manage striatal DA levels, working as a reservoir for circulating levodopa …”

“…[38][39][40] Moreover, relevant to PD, astrocytes can manage striatal DA levels, working as a reservoir for circulating levodopa. 41 On this view, a different time course in sham-versus 6-OHDA-lesioned rats might reflect different mechanisms (synaptic vs nonsynaptic) by which DA levels change in response to TMS. Taken together, these data suggest that glial cells may have a role in iTBS effects on corticostriatal plasticity.…”

In vivo protein targets for increased quinoprotein adduct formation in aged substantia nigra

“…Given the presence of high concentration of DTT in the lysis buffer and the selective enrichment in aged brains, the quinone modification of GFAP is unlikely a result of the post-lysis artifact. It has been reported that astrocytes will uptake extrcellular DA (Asanuma et al, 2014;Inazu et al, 1999a,b). Therefore, internalized DA may oxidize and modify GFAP in astrocytes, and the accumulation of quinone modified GFAP during aging process may account for the detection of quinone modified GFAP in our study.…”

What Mechanisms Are Responsible for the Reuptake of Levodopa-Derived Dopamine in Parkinsonian Striatum?

“…In cultured astrocytes from rat cortex, a NET blocker inhibits uptake of dopamine and norepinephrine; the effect was not seen with a DAT blocker, indicating dopamine uptake is performed by NETs in astrocytes (Takeda et al, 2002). In a parkinsonian state, the number of astrocytes increase with dopaminergic denervation (Teismann and Schulz, 2004; Asanuma et al, 2014). Thus, increased NET activity of dopamine transport in the dopamine-denervated striatum may occur at astrocytes, not at norepinephrinergic neurons (Figure 2B).…”