Single Administration of Tripeptide α-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 (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 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 α-MSH(11–13) on secondary lesion volume determined in cresyl violet stained sections (intraperitoneal injection 30 min after insult of 1 mg/kg α-MSH(11–13) or 0.9% NaCl) showed a considerable smaller trauma in α-MSH(11–13) injected mice. The expression of the inflammatory markers TNF-α and IL-1β 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 α-MSH(11–13) administration offers a promising neuroprotective property by modulation of inflammation and prevention of apoptosis after traumatic brain injury.

Progranulin protects against exaggerated axonal injury and astrogliosis following traumatic brain injury

“…Experimental TBI was performed using the CCI model essentially as described (Schaible et al, ). Briefly, anesthesia was induced by 4% (v/v) and maintained by 2% (v/v) isoflurane gas exposure, mice were fixed in a stereotactic frame and a large craniotomy (4 × 4 mm) was drilled.…”

2‐Methoxyestradiol confers neuroprotection and inhibits a maladaptive HIF‐1α response after traumatic brain injury in mice

“…The quantification of the functional outcome was assessed using a modified 15‐point neurological severity score as described (Schaible et al . ). Healthy animals pass the test with 0 or 1 point, whereas severely impaired mice receive up to 15 points.…”

“…Neuroscore and Rotarod performance test (Accelerating ROTA-ROD, Harvard Apparatus GmbH, Holliston, MA, USA) were evaluated pre-injection and pre-mortem. The quantification of the functional outcome was assessed using a modified 15-point neurological severity score as described (Schaible et al 2013). Healthy animals pass the test with 0 or 1 point, whereas severely impaired mice receive up to 15 points.…”

Neuropeptides and Microglial Activation in Inflammation, Pain, and Neurodegenerative Diseases

“…Subsequently, α -MSH and α -MSH 11–13 were also demonstrated to reduce the release of TNF- α and NO and the expression of TNF- α and inducible nitric oxide synthase (iNOS) induced by costimulation of N9 cells with Amyloid- β (A β ) and IFN- γ [28], further supporting its role as an anti-inflammatory agent. Since then, melanocortins have proven to be anti-inflammatory and neuroprotective in vivo in several experimental models of nervous tissue damage, including brain ischemia [29–31] and traumatic brain injury, where neuroprotection exerted by α -MSH (11–13) was associated with decreased microglial activation [32], suggesting a contribution of local immunomodulation to the overall neuroprotective effect.…”