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Disruption of the serotonergic system after neonatal hypoxia-ischemia in a rodent model.

Buller KM, Wixey JA, Reinebrant HE - Neurol Res Int (2012)

Bottom Line: Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates.Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia.These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen.

View Article: PubMed Central - PubMed

Affiliation: Royal Brisbane and Women's Hospital, The University of Queensland, Herston, QLD 4029, Australia.

ABSTRACT
Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram depicting the major pathways involved in the synthesis, release, re-uptake and metabolism of serotonin in serotonergic neurons. Components of the figure have been modified from Motifolio. TpH: tryptophan hydroxylase; 5-HTP: 5-hydroxy-L-tryptophan; 5-HT: serotonin; SERT: serotonin transporter; MAO: monoamine oxidase; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTR: serotonergic receptor.
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fig1: Schematic diagram depicting the major pathways involved in the synthesis, release, re-uptake and metabolism of serotonin in serotonergic neurons. Components of the figure have been modified from Motifolio. TpH: tryptophan hydroxylase; 5-HTP: 5-hydroxy-L-tryptophan; 5-HT: serotonin; SERT: serotonin transporter; MAO: monoamine oxidase; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTR: serotonergic receptor.

Mentions: Serotonin is synthesised in the brain in serotonergic neurons from the amino acid L-tryptophan and its metabolite 5-hydroxytryptophan (5-HTP). Synthesis occurs via tryptophan hydroxylase (TpH), 5-HT's rate-limiting enzyme and a second enzyme amino acid decarboxylase. Two isoforms of TpH are known to exist (TpH1 and TpH2) but only TpH2 is found in the brain [52]. The major regulator of 5-HT levels in the brain is the serotonin transporter (SERT). The transporter consists of 12 transmembrane domains that span the presynaptic membrane of 5-HT-releasing cells [53]. Localised on the presynaptic membrane of serotonergic neurons, SERT terminates serotonergic signalling by the efficient reuptake of extracellular serotonin back into the presynaptic neuron (Figure 1) thereby controlling the duration of action and post-synaptic signalling of 5-HT in the brain. Consequently, SERT is a major target for drugs such as selective serotonin reuptake inhibitors (SSRIs) that can increase 5-HT availability in the brain and are useful drugs in the treatment of depression. Serotonin is also broken down by monoamine oxidase (MAO) enzymes, preferentially MAO-A, into 5-hydroxyindoleacetic acid (5-HIAA); serotonin's major metabolite.


Disruption of the serotonergic system after neonatal hypoxia-ischemia in a rodent model.

Buller KM, Wixey JA, Reinebrant HE - Neurol Res Int (2012)

Schematic diagram depicting the major pathways involved in the synthesis, release, re-uptake and metabolism of serotonin in serotonergic neurons. Components of the figure have been modified from Motifolio. TpH: tryptophan hydroxylase; 5-HTP: 5-hydroxy-L-tryptophan; 5-HT: serotonin; SERT: serotonin transporter; MAO: monoamine oxidase; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTR: serotonergic receptor.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3306961&req=5

fig1: Schematic diagram depicting the major pathways involved in the synthesis, release, re-uptake and metabolism of serotonin in serotonergic neurons. Components of the figure have been modified from Motifolio. TpH: tryptophan hydroxylase; 5-HTP: 5-hydroxy-L-tryptophan; 5-HT: serotonin; SERT: serotonin transporter; MAO: monoamine oxidase; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTR: serotonergic receptor.
Mentions: Serotonin is synthesised in the brain in serotonergic neurons from the amino acid L-tryptophan and its metabolite 5-hydroxytryptophan (5-HTP). Synthesis occurs via tryptophan hydroxylase (TpH), 5-HT's rate-limiting enzyme and a second enzyme amino acid decarboxylase. Two isoforms of TpH are known to exist (TpH1 and TpH2) but only TpH2 is found in the brain [52]. The major regulator of 5-HT levels in the brain is the serotonin transporter (SERT). The transporter consists of 12 transmembrane domains that span the presynaptic membrane of 5-HT-releasing cells [53]. Localised on the presynaptic membrane of serotonergic neurons, SERT terminates serotonergic signalling by the efficient reuptake of extracellular serotonin back into the presynaptic neuron (Figure 1) thereby controlling the duration of action and post-synaptic signalling of 5-HT in the brain. Consequently, SERT is a major target for drugs such as selective serotonin reuptake inhibitors (SSRIs) that can increase 5-HT availability in the brain and are useful drugs in the treatment of depression. Serotonin is also broken down by monoamine oxidase (MAO) enzymes, preferentially MAO-A, into 5-hydroxyindoleacetic acid (5-HIAA); serotonin's major metabolite.

Bottom Line: Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates.Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia.These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen.

View Article: PubMed Central - PubMed

Affiliation: Royal Brisbane and Women's Hospital, The University of Queensland, Herston, QLD 4029, Australia.

ABSTRACT
Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

No MeSH data available.


Related in: MedlinePlus