Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model

Back, A.; Tupper, Kelsey Y.; Bai, Tao; Chiranand, Paulpoj; Goldenberg, Fernando D.; Frank, Jeffrey I.; Brorson, James R.

doi:10.1179/1743132811y.0000000046

Cited by 31 publications

(27 citation statements)

References 25 publications

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“…Animal studies also support the cytotoxic aspect of AHE related brain edema (Norenberg 1977;Traber et al 1987;Gove et al 1997;Matkowskyj et al 1999;Venkatasubramanian et al 2001;Chavarria et al 2010). Exposure of rat cerebral cortical slices or organotypic slice cultures from mouse forebrain to 1-10 mM ammonia was shown to induce astrocyte swelling (Ganz et al 1989;Back et al 2011). Additionally, treatment of cultured astrocytes with a pathophysiologically relevant concentration of ammonia was shown to induce cell swelling (Norenberg et al 1991Reinehr et al 2007;Andersson et al 2009;Konopacka et al 2009), strongly supporting the view that the brain edema in AHE is predominantly, if not exclusively, cytotoxic.…”

Section: Discussionmentioning

confidence: 71%

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Increased toll‐like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy

Jayakumar

Tong

Curtis

et al. 2013

Journal of Neurochemistry

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Astrocyte swelling and the subsequent increase in intracranial pressure and brain herniation are major clinical consequences in patients with acute hepatic encephalopathy (AHE). We recently reported that conditioned media (CM) from brain endothelial cells (ECs) exposed to ammonia, a mixture of cytokines (CKs) or lipopolysaccharide (LPS), when added to astrocytes caused cell swelling. In the present study we investigated the possibility that ammonia and inflammatory agents activate the toll-like receptor 4 (TLR4) in ECs, resulting in the release of factors that ultimately cause astrocyte swelling. We found a significant increase in TLR4 protein expression when ECs were exposed to ammonia, CKs or LPS alone, while exposure of ECs to a combination of these agents potentiated such effects. Additionally, astrocytes exposed to CM from TLR4-silenced ECs that were treated with ammonia, CKs or LPS, resulted in a significant reduction in astrocyte swelling. TLR4 protein upregulation was also detected in rat brain ECs after treatment with the liver toxin thioacetamide (TAA), and that TAA-treated TLR4 knock-out mice exhibited a reduction in brain edema. These studies strongly suggest that ECs significantly contribute to the astrocyte swelling/brain edema in AHE, likely as a consequence of increased TLR4 protein expression by blood-borne noxious agents.

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Section: Discussionmentioning

confidence: 71%

“…; Back et al . ). Additionally, treatment of cultured astrocytes with a pathophysiologically relevant concentration of ammonia was shown to induce cell swelling (Norenberg et al .…”

Section: Discussionmentioning

confidence: 97%

Increased toll‐like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy

Jayakumar

Tong

Curtis

et al. 2013

Journal of Neurochemistry

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“…Cerebrocortical organotypic slice cultures from newborn pups of C57BL/6 mice were generated and maintained as previously described [19]. Slices (initial thickness 385 µm) were from frontal brain areas including motor cortex.…”

Section: Methodsmentioning

confidence: 99%

Tunicamycin produces TDP-43 cytoplasmic inclusions in cultured brain organotypic slices

Leggett

McGehee

Mastrianni

et al. 2012

Journal of the Neurological Sciences

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The cellular distribution of TAR DNA binding protein (TDP-43) is disrupted in several neurodegenerative disorders, including frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U subtype) and amyotrophic lateral sclerosis (ALS). In these conditions, TDP-43 is found in neuronal cytoplasmic inclusions, with loss of the normal nuclear expression. The mechanisms leading to TDP-43 redistribution and its role in disease pathophysiology remain unknown. We describe an in vitro neural tissue model that reproduces TDP-43 relocalization and inclusion formation. Two week-old coronal organotypic mouse brain slice cultures were treated with tunicamycin for 7 days. In cortical regions of treated slice cultures, cytoplasmic inclusions of TDP-43 immunoreactivity were observed, with loss of nuclear TDP-43 immunoreactivity. These inclusions were found in both astrocytes and neurons, and were of both skein-like and round morphologies. In contrast, TDP-43 cytoplasmic inclusions were not found in slices treated with staurosporine to induce apoptosis, or with trans-4-carboxy-L-proline (PDC) to induce chronic glutamate excitotoxicity. Furthermore, TDP-43 cytoplasmic inclusions did not co-localize with cleaved caspase-3, suggesting that TDP-43 mislocalization does not generally accompany caspase activation or apoptosis. The induction of TDP-43 cytoplasmic translocation in cerebrocortical slice cultures by tunicamycin provides a platform for further mechanistic investigations of pathological processing of TDP-43.

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“…Treatment of cultured astrocytes with a pathophysiologically relevant concentration of ammonia (5 mM) was shown to induce cell swelling [8, 16–19] (for review, see [8]). Exposure of rat cerebral cortical slices or organotypic slice cultures from mouse forebrain to 1–10 mM ammonia were also shown to induce astrocyte swelling [14, 15]. …”

Section: Discussionmentioning

confidence: 99%

“…Animal studies also support the cytotoxic aspect of ALF-related brain edema (for review, see [13]). Further, exposure of rat cerebral cortical slices or organotypic slice cultures from mouse forebrain to 1–10 mM ammonia was shown to induce astrocyte swelling [14, 15]. Additionally, treatment of cultured astrocytes with a pathophysiologically relevant concentration of ammonia (5 mM) was shown to induce cell swelling [8, 16–19].…”

Section: Introductionmentioning

confidence: 99%

Brain edema in acute liver failure: Role of neurosteroids

Jayakumar¹,

Ruíz-Cordero²,

Tong³

et al. 2013

Archives of Biochemistry and Biophysics

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Brain edema is a major neurological complication of acute liver failure (ALF) and swelling of astrocytes (cytotoxic brain edema) is the most prominent neuropathological abnormality in this condition. Elevated brain ammonia level has been strongly implicated as an important factor in the mechanism of astrocyte swelling/brain edema in ALF. Recent studies, however, have suggested the possibility of a vasogenic component in the mechanism in ALF. We therefore examined the effect of ammonia on blood-brain barrier (BBB) integrity in an in vitro co-culture model of the BBB (consisting of primary cultures of rat brain endothelial cells and astrocytes). We found a minor degree of endothelial permeability to dextran fluorescein (16.2%) when the co-culture BBB model was exposed to a pathophysiological concentration of ammonia (5 mM). By contrast, lipopolysaccharide (LPS), a molecule well-known to disrupt the BBB, resulted in an 87% increase in permeability. Since increased neurosteroid biosynthesis has been reported to occur in brain in ALF, and since neurosteroids are known to protect against BBB breakdown, we examined whether neurosteroids exerted any protective effect on the slight permeability of the BBB after exposure to ammonia. We found that a nanomolar concentration (10 nM) of the neurosteroids allopregnanolone (THP) and tetrahydrodeoxycorticosterone (THDOC) significantly reduced the ammonia-induced increase in BBB permeability (69.13 and 58.64%, respectively). On the other hand, we found a marked disruption of the BBB when the co-culture model was exposed to the hepatotoxin azoxymethane (218.4%), but not with other liver toxins commonly used as models of ALF (thioacetamide and galactosamine, showed a 29.3 and 30.67% increase in permeability, respectively). Additionally, THP and THDOC reduced the effect of TAA and galactosamine on BBB permeability, while no BBB protective effect was observed following treatment with azoxymethane. These findings suggest that ammonia does not cause a significant BBB disruption, and that the BBB is intact in the TAA or galactosamine-induced animal models of ALF, likely due to the protective effect of neurosteroids that are synthesized in brain in the setting of ALF. However, caution should be exercised when using azoxymethane as an experimental model of ALF as it caused a severe breakdown of the BBB, and neurosteriods failed to protect against this.

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Ammonia-induced brain swelling and neurotoxicity in an organotypic slice model

Cited by 31 publications

References 25 publications

Increased toll‐like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy

Increased toll‐like receptor 4 in cerebral endothelial cells contributes to the astrocyte swelling and brain edema in acute hepatic encephalopathy

Tunicamycin produces TDP-43 cytoplasmic inclusions in cultured brain organotypic slices

Brain edema in acute liver failure: Role of neurosteroids

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