title: Cross-talk between neurons and astrocytes in response to bilirubin: adverse secondary impacts.
abstract: Previous studies using monotypic nerve cell cultures have shown that bilirubin-induced neurological dysfunction (BIND) involves apoptosis and necrosis-like cell death, following neuritic atrophy and astrocyte activation,and that glycoursodeoxycholic acid (GUDCA) has therapeutic efficacy against BIND. Cross-talk between neurons and astrocytes may protect or aggravate neurotoxicity by unconjugated bilirubin (UCB). In a previous work we have shown that bidirectional signaling during astrocyte-neuron recognition attenuates neuronal damage by UCB. Here, we investigated whether the establishment of neuron-astrocyte homeostasis prior to cell exposure to UCB was instead associated with a lower resistance of neurons to UCB toxicity, and if the pro-survival properties of GUDCA were replicated in that experimental model. We have introduced a 24 h adaptation period for neuron-glia communication prior to the 48 h treatment with UCB. In such conditions, UCB induced glial activation, which aggravated neuronal damage, comprising increased apoptosis,cell demise and neuritic atrophy, which were completely prevented in the presence of GUDCA. Neuronal multidrug resistance-associated protein 1 expression and tumor necrosis factor-a secretion, although unchanged by UCB, increased in the presence of astrocytes. The rise in S100B and nitric oxide in the co-cultures medium may have contributed to UCB neurotoxicity. Since the levels of these diffusible molecules did not change by GUDCA we may assume that they are not directly involved in its beneficial effects. Data indicate that astrocytes, in an indirect neuron-astrocyte co-culture model and after homeostatic setting regulation of the system, are critically influencing neurodegeneration by UCB, and support GUDCA for the prevention of BIND.
authors.forename: Ana Sofia
authors.initials: AS
authors.lastname: Falcão
authors.forename: Rui F M
authors.initials: RF
authors.lastname: Silva
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Vaz
authors.forename: Cátia
authors.initials: C
authors.lastname: Gomes
authors.forename: Adelaide
authors.initials: A
authors.lastname: Fernandes
authors.forename: Andreia
authors.initials: A
authors.lastname: Barateiro
authors.forename: Claudio
authors.initials: C
authors.lastname: Tiribelli
authors.forename: Dora
authors.initials: D
authors.lastname: Brites
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000633:toxicity*; D001253:Astrocytes / Q000187:drug effects* / Q000502:physiology; D001663:Bilirubin / Q000633:toxicity*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects* / Q000502:physiology; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018920:Coculture Techniques; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D017208:Rats, Wistar; D064568:S100 Calcium Binding Protein beta Subunit / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D001663:Bilirubin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018696:Neuroprotective Agents; D009569:Nitric Oxide; D064568:S100 Calcium Binding Protein beta Subunit; D014409:Tumor Necrosis Factor-alpha; D014580:Ursodeoxycholic Acid; C579158:S100b protein, rat; C024033:glycoursodeoxycholic acid; C421109:multidrug resistance-associated protein 1