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Single administration of tripeptide ?-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice.

ABSTRACT: Following traumatic brain injury (TBI) neuroinflammatory processes promote neuronal cell loss. Alpha-melanocyte-stimulating hormone (?-MSH) is a neuropeptide with immunomodulatory properties, which may offer neuroprotection. Due to short half-life and pigmentary side-effects of ?-MSH, the C-terminal tripeptide ?-MSH(11-13) may be an anti-inflammatory alternative. The present study investigated the mRNA concentrations of the precursor hormone proopiomelanocortin (POMC) and of melanocortin receptors 1 and 4 (MC1R/MC4R) in naive mice and 15 min, 6, 12, 24, and 48 h after controlled cortical impact (CCI). Regulation of POMC and MC4R expression did not change after trauma, while MC1R levels increased over time with a 3-fold maximum at 12 h compared to naive brain tissue. The effect of ?-MSH(11-13) on secondary lesion volume determined in cresyl violet stained sections (intraperitoneal injection 30 min after insult of 1 mg/kg ?-MSH(11-13) or 0.9% NaCl) showed a considerable smaller trauma in ?-MSH(11-13) injected mice. The expression of the inflammatory markers TNF-? and IL-1? as well as the total amount of Iba-1 positive cells were not reduced. However, cell branch counting of Iba-1 positive cells revealed a reduced activation of microglia. Furthermore, tripeptide injection reduced neuronal apoptosis analyzed by cleaved caspase-3 and NeuN staining. Based on the results single ?-MSH(11-13) administration offers a promising neuroprotective property by modulation of inflammation and prevention of apoptosis after traumatic brain injury.

SUBMITTER: Schaible EV

PROVIDER: S-EPMC3733710 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Single administration of tripeptide α-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice.

Schaible Eva-Verena EV Steinsträßer Arne A Jahn-Eimermacher Antje A Luh Clara C Sebastiani Anne A Kornes Frida F Pieter Dana D Schäfer Michael K MK Engelhard Kristin K Thal Serge C SC

PloS one 20130805 8

Following traumatic brain injury (TBI) neuroinflammatory processes promote neuronal cell loss. Alpha-melanocyte-stimulating hormone (α-MSH) is a neuropeptide with immunomodulatory properties, which may offer neuroprotection. Due to short half-life and pigmentary side-effects of α-MSH, the C-terminal tripeptide α-MSH(11-13) may be an anti-inflammatory alternative. The present study investigated the mRNA concentrations of the precursor hormone proopiomelanocortin (POMC) and of melanocortin recepto ...[more]

PMID: 23940690

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Project description:Traumatic brain injury induces potent inflammatory responses that can exacerbate secondary blood-brain barrier (BBB) disruption, neuronal injury, and neurological dysfunction. Dexmedetomidine is a novel α2-adrenergic receptor agonist that exert protective effects in various central nervous system diseases. The present study was designed to investigate the neuroprotective action of dexmedetomidine in a mouse traumatic brain injury model, and to explore the possible mechanisms. Adult male C57BL/6J mice were subjected to controlled cortical impact. After injury, animals received 3 days of consecutive dexmedetomidine therapy (25 µg/kg per day). The modified neurological severity score was used to assess neurological deficits. The rotarod test was used to evaluate accurate motor coordination and balance. Immunofluorescence was used to determine expression of ionized calcium binding adapter molecule-1, myeloperoxidase, and zonula occluden-1 at the injury site. An enzyme linked immunosorbent assay was used to measure the concentration of interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6. The dry-wet weight method was used to measure brain water content. The Evans blue dye extravasation assay was used to measure BBB disruption. Western blot assay was used to measure protein expression of nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3), caspase-1 p20, IL-1β, nuclear factor kappa B (NF-κB) p65, occluding, and zonula occluden-1. Flow cytometry was used to measure cellular apoptosis. Results showed that dexmedetomidine treatment attenuated early neurological dysfunction and brain edema. Further, dexmedetomidine attenuated post-traumatic inflammation, up-regulated tight junction protein expression, and reduced secondary BBB damage and apoptosis. These protective effects were accompanied by down-regulation of the NF-κB and NLRP3 inflammasome pathways. These findings suggest that dexmedetomidine exhibits neuroprotective effects against acute (3 days) post-traumatic inflammatory responses, potentially via suppression of NF-κB and NLRP3 inflammasome activation.

Project description:BackgroundNeonatal seizures commonly caused by hypoxia could lead to brain injury and cognitive deficits. Quercetin could cross the blood brain barrier and exerts neuroprotective effects in many neurological disease settings. In this study, we aim to investigate the role of quercetin in attenuating cognitive impairment following hypoxia-induced neonatal seizure (HINS).MethodSprague-Dawley rats at P7 were exposed to a premixed gas in a hypoxic chamber to induce brain injury, and then continuously administered with quercetin for 21 days. Pentylenetetrazol kindling was used to induce seizures in the evolution. After the hypoxic lesion was stablished, anxiety-related behavior of rats after HINS was assessed using open field test. Memory impairment of rats after HINS was evaluated using novel object-recognition test and elevated plus maze test. The serum and hippocampal concentrations of TNF-a, iNOS, IL-6 MCP-1, and IL-1β were measured using ELISA. The mRNA expression levels of TNF-a, iNOS, IL-6 in the hippocampus were determined using qRT-PCR. The protein levels of TLR4, NF-κB p65, and p-NF-κB p65 in the hippocampus were determined using Western blot.ResultsQuercetin administration significantly reduced later-life seizure susceptibility, anxiety-related behavior, and memory impairments in the rats following the HINS when compared to the HINS group without treatment. Both serum and hippocampal proinflammatory cytokines levels were significantly elevated in the rat after HINS. TLR4 protein expressions were increased in the HINS group when compared to control group, and decreased in the group of quercetin. The protein level of p-NF-κB p65 was significantly lower in the quercetin group compared to the HINS group.ConclusionWe demonstrated that Quercetin significantly reduced susceptibility to later-life seizures. Quercetin could downregulate inflammatory response through TLR4/ NF-κB pathway, thereby attenuating HINS-induced anxiety, hippocampal memory impairment, and cognitive impairment in later life following HINS.

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Single administration of tripeptide ?-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice.

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Single administration of tripeptide α-MSH(11-13) attenuates brain damage by reduced inflammation and apoptosis after experimental traumatic brain injury in mice.

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