Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke

Nam, Min‐Ho; Cho, Jongwook; Kwon, Dae‐Hyuk; Park, Jiyoung; Woo, Junsung; Lee, Jung Moo; Lee, Sang‐Won; Ko, Heung Kyu; Won, Woojin; Kim, Ra Gyung; Song, Hanlim; Oh, Soo‐Jin; Choi, Ji Won; Park, Ki Duk; Park, Eun Kyung; Jung, Haejin; Kim, Hyung-Seok; Lee, Min-Cheol; Yun, Mijin; Lee, C. Justin; Kim, Hyoung-Ihl

doi:10.1016/j.celrep.2020.107975

Cited by 28 publications

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“…1d). The increased MCT1 expression in GFAP-positive reactive astrocytes was also observed in an in vivo model of neuroinflammation induced by unilateral adenovirus injection into the motor and somatosensory cortices of the rat brain 8 (Fig. 1g-j).…”

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confidence: 59%

“…precedes neuronal degeneration or death 1,2 and even directly causes extensive neuronal death [4][5][6] . Recent studies have also reported that reactive astrocytes aberrantly produce GABA to inhibit neighboring neuronal activity and glucose metabolism [7][8][9][10] , which critically contributes to neuronal dysfunction in AD 7,11 . Therefore, in vivo imaging of reactive astrogliosis should have a considerable diagnostic value for the early stages of AD.…”

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confidence: 99%

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Visualization of reactive astrocytes in living brain of Alzheimer’s disease patient

et al. 2021

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An early appearance of reactive astrocytes is a hallmark of Alzheimer's disease (AD), providing a substrate for early diagnostic neuroimaging targets. However, there is no clinically validated neuroimaging probe to visualize the reactive astrogliosis in the human brain in vivo. Here, we report that PET/CT imaging with 11C-acetate and 18F-5 fluorodeoxyglucose (18F-FDG) functionally visualizes the reactive astrocyte-mediated neuronal hypometabolism in the brains with neuroinflammation and AD. We demonstrate that reactive astrocytes excessively absorb acetate through elevated monocarboxylate transporter-1 (MCT1), leading to aberrant GABA synthesis and release which suppresses neuronal glucose uptake through decreased glucose 10 transporter-3 (GLUT3) in both animal and human brains. We propose the non-invasive functional PET/CT imaging for astrocytic acetate-hypermetabolism and neuronal glucose-hypometabolism as an advanced diagnostic strategy for early stages of AD.

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confidence: 99%

Visualization of reactive astrocytes in living brain of Alzheimer’s disease patient

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“…In the same study, we also found that long-term treatment (> 2 weeks) of selegiline did not show any therapeutic effect, which is due to compensatory up-regulation of astrocytic GABA synthesis (via diamine oxidase) following chronic treatment with an irreversible MAO-B inhibitor, while long-term treatment of reversible MAO-B inhibitor did not turn on this compensatory metabolism (Park et al, 2019). Furthermore, in our recent study a long-term treatment of KDS2010 showed a dramatic effect on post-stroke recovery when it was accompanied by rehabilitation training (Nam et al, 2020). The difference in therapeutic effects in AD between reversible and irreversible MAO-B inhibitors is consistent with current findings in PD.…”

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confidence: 77%

“…For example, no difference in dopamine level between MAO-B-deficient mice and wild-type mice (Fornai, Chen, Giorgi, Gesi, Alessandri & Shih, 1999), and no alteration in dopamine level by selegiline treatment (Lamensdorf, Youdim & Finberg, 1996). In addition to these two possibilities, we have reported the critical role of MAO-B in GABA synthesis in reactive astrocytes (Heo et al, 2020;Jo et al, 2014;Nam et al, 2020;Yoon et al, 2014a). Reactive astrocytes produce excess amount of GABA through MAO-B and tonically release GABA to suppress neighboring DA neurons in SNpc, which leads to reduced TH level and DA synthesis, finally causing parkinsonian motor symptoms (Heo et al, 2020).…”

Section: Discussionmentioning

confidence: 86%

“…Therefore, MAO-B has been believed to degrade dopamine which is a monoamine neurotransmitter and MAO-B inhibitors have been believed to exert anti-Parkinsonian effects by blocking the degradation of dopamine (Schapira, 2011). In contrast, recent studies have demonstrated that MAO-B expression is dramatically increased in reactive astrocytes and that MAO-B is responsible for astrocytic GABA synthesis through the putrescine degradation pathway (Heo et al, 2020;Jo et al, 2014;Nam et al, 2020;Yoon et al, 2014a). A recent study revealed that MAO-B-mediated astrocytic GABA is critically involved in the pathology of PD.…”

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confidence: 95%

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KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease

Nam

Park

Song

et al. 2020

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AbstractBackground and PurposeMonoamine oxidase-B (MAO-B) is a long-standing therapeutic target for Parkinson’s disease (PD), however, previous clinical studies demonstrated discouraging effects of currently available irreversible MAO-B inhibitors. Since KDS2010, a novel, potent, selective, and reversible MAO-B inhibitor, has been developed, here we tested its therapeutic potential in animal models of PD.Experimental ApproachWe designed and synthesized α-aminoamide derivatives and compared the specificity to MAO-B and reversibility of each compound with KDS2010. To investigate the in vivo therapeutic effect, we used MPTP mouse model with two different regimes of 3-day administration (pre-treatment or post-treatment) and 30-day administration. We assessed the therapeutic potential using behavioral and immunohistochemical analyses. Additionally, the functional recovery by KDS2010 was tested in 6-hydroxydopamine-induced and A53T-alpha-synuclein overexpression models. Lastly, to validate the potential as a clinical drug candidate, we investigated the pharmacokinetics and toxicity of KDS2010 in non-human primates.Key ResultsKDS2010 showed the highest potency, specificity, and reversibility among the α-aminoamide derivatives, with high bioavailability (>100%) and BBB permeability. KDS2010 also showed significant neuroprotective and anti-neuroinflammatory effects in the nigrostriatal pathway, leading to an alleviation of MPTP-induced parkinsonism in all administration regimes. In particular, the therapeutic effect of KDS2010 was superior to selegiline, an irreversible MAO-B inhibitor. KDS2010 also showed a potent therapeutic effect in 6-hydroxydopamine and A53T models. Moreover, KDS2010 showed virtually no toxicity or side-effect in non-human primates.Conclusion and ImplicationsKDS2010 shows excellent therapeutic potential and safety in various PD animal models. KDS2010, therefore, could be a next-generation therapeutic candidate for PD.Representative SchematicWhat is already knownKDS2010 is a recently developed potent, selective, and reversible MAO-B inhibitor.MAO-B is critical for PD pathology through astrocytic GABA and H2O2 synthesis.What this study addsKDS2010 treatment dramatically recovers from PD-related pathology and motor deficit after pre- and post-treatment regimes in several animal models of PD.KDS2010 exhibits low toxicity and excellent pharmacokinetic profile in non-human primates.What is the clinical significance?KDS2010 is a safe and promising therapeutic candidate for Parkinson’s disease.Reversible MAO-B inhibitors could be more effective for treatment of Parkinson’s disease, overcoming the short-lived actions of irreversible MAO-B inhibitors.

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Inhibition of monoamine oxidase B prevents reactive astrogliosis and scar formation in stab wound injury model

Chun

Lim

Park

et al. 2021

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Reactive astrocytes manifest molecular, structural, and functional alterations under various pathological conditions. We have previously demonstrated that the reactive astrocytes of the stab wound injury model (STAB) display aberrant cellular gamma‐aminobutyric acid (GABA) content and tonic GABA release, whereas the active astrocytes under enriched environment (EE) express high levels of proBDNF. However, the role of monoamine oxidase B (MAO‐B) in reactive astrogliosis and hypertrophy still remains unknown. Here, we investigate the role of MAO‐B, a GABA‐producing enzyme, in reactive astrogliosis in STAB. We observed that the genetic removal of MAO‐B significantly reduced the hypertrophy, scar formation, and GABA production of reactive astrocytes, whereas the MAO‐B overexpression under glial fibrillary acidic protein (GFAP) promoter enhanced the levels of GFAP and GABA. Furthermore, we found that one of the by‐products of the MAO‐B action, H2O2, but not GABA, was sufficient and necessary for the hypertrophy of reactive astrocytes. Notably, we identified two potent pharmacological tools to attenuate scar‐forming astrogliosis—the recently developed reversible MAO‐B inhibitor, KDS2010, and an H2O2 scavenger, crisdesalazine (AAD‐2004). Our results implicate that inhibiting MAO‐B activity has dual beneficial effects in preventing astrogliosis and scar‐formation under brain injury, and that the MAO‐B/H2O2 pathway can be a useful therapeutic target with a high clinical potential.

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Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke

Abstract: In the originally published version of this article, the author name Jung Moo Lee was spelled incorrectly. This has now been corrected online.

Cited by 28 publications

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Visualization of reactive astrocytes in living brain of Alzheimer’s disease patient

Visualization of reactive astrocytes in living brain of Alzheimer’s disease patient

KDS2010, a newly developed reversible MAO-B inhibitor, as an effective therapeutic candidate for Parkinson’s disease

Inhibition of monoamine oxidase B prevents reactive astrogliosis and scar formation in stab wound injury model

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