ABSTRACT
Title
Palmitoylethanolamide is able to attenuate astrocyte activation and neuroinflammation in an in vivo model of Alzheimer’s disease
Authors
C. Scuderi1, M. Valenza2, P. Ratano1, A. Steardo1, G. Esposito1, P. Campolongo1, M.R. Carratù2 and L. Steardo1
1Dept. of Physiology and Pharmacology "V. Erspamer" - Sapienza University of Rome, Italy
2Dept. of Pharmacology and Human Physiology - University of Bari, Italy
1Dept. of Physiology and Pharmacology "V. Erspamer" - Sapienza University of Rome, Italy
2Dept. of Pharmacology and Human Physiology - University of Bari, Italy
Abstract
A large amount of evidence suggests that neuroinflammation is crucially involved in the course of many neurodegenerative diseases, including Alzheimer's disease (AD). Acute neuroinflammatory responses are generally beneficial to the central nervous system. However, when glial activation inappropriately persists long after the initial injury, the prolonged condition of neuroinflammation induces changes in the pathophysiological significance of the glial reaction, so that inflammation may inexorably turn into a detrimental process [1]. In neurodegenerative disorders, inflammation may be triggered by the accumulation of abnormal proteins or by signals emanating from injured neurons. In this context, the extracellular deposition of beta amyloid (Aβ) in the form of amyloid plaques is clearly among the most potent inducers of neuroinflammation [2]. Indeed, besides cytotoxic mechanisms directly impacting on neurons, Aβ-induced glial activation promotes release of inflammatory molecules that may act autocrinally, to self-perpetuate reactive gliosis, and paracrinally, to damage neighboring neurons, thereby amplifying neuropathological lesions [3]. On the basis of these consideration, it is now patent that any compound able to modulate astrocyte activation might be considered as a novel therapeutic tool. Among these molecules, palmitoylethanolamide (PEA) has attracted much attention for its proven anti-inflammatory and neuroprotective properties. PEA, a naturally occurring amide of ethanolamine and palmitic acid, is a lipid messenger that mimics several endocannabinoid-driven actions, even though it does not bind to cannabinoid receptors [4]. Recent findings demonstrate the efficiency of PEA to blunt astrogliosis in an in vitro model of beta amyloid toxicity [5].
The purpose of the present study was to explore whether or not PEA is able to attenuate Aβ-induced neuroinflammationin an in vivo model of AD.
Adult male Sprague-Dowley rats (250-300g) were anesthetized, placed in a stereotaxic frame and inoculated with 5µg/situ of human Aβ peptide fragment (1-42) into the CA1 region of the hippocampus (coordinates relative to the bregma: AP -3 mm; ML ± 2 mm; DV -2.2 mm). Control rats were treated according to the same procedure, and they were inoculated with an equivalent volume of artificial cerebrospinal fluid.
PEA (10mg/kg) was i.p. administered for 7 consecutive days starting from the day of surgery.
After 24h from the last administration, rats were sacrificed by decapitation or transcardiac perfusion. Obtained brains were processed for western blot and immunofluorescence analyses.
In order to test the effect of PEA on Aβ-induced astrogliosis, we explored the expression of GFAP and S100B, specific markers of astrocyte activity. We observed a marked increase in both GFAP and S100B expression after Aβ challenge. This enhancement was significantly attenuated by PEA treatment.
Another set of experiments was aimed at assessing the effect of PEA on the production of inflammatory factors induced by Aβ. Peptide injection resulted in a significant increase in iNOS and COX-2 expression. Such protein increase paralleled pro-inflammatory cytokines up-release, such as IL1β and TNFα. Also in this case PEA antagonized the enhancement of both expression and release of all pro-inflammatory molecules detected.
In conclusion, the current study suggests the ability of PEA to mitigate astrocyte activation and neuroinflammatory process in an in vivo model of AD.
The relevance of these results resides in the hypothesis that pharmacological attenuation of excessive and prolonged reactive gliosis may serve as innovative strategies for therapies aimed at antagonizing the course of AD.
[1] Glass et al. Cell. 2010; 140: 918-34
[2] Craft et al. Glia. 2006; 53: 484–90
[3] Wyss-Coray and Mucke. Neuron. 2002; 35: 419-32
[4] Mackie and Stella. AAPS J. 2006; 8: E298-306
[5] Scuderi et al. J Cell Mol Med. 2011 Jan 21. doi: 10.1111/j.1582-4934.2011.01267.x.
The purpose of the present study was to explore whether or not PEA is able to attenuate Aβ-induced neuroinflammationin an in vivo model of AD.
Adult male Sprague-Dowley rats (250-300g) were anesthetized, placed in a stereotaxic frame and inoculated with 5µg/situ of human Aβ peptide fragment (1-42) into the CA1 region of the hippocampus (coordinates relative to the bregma: AP -3 mm; ML ± 2 mm; DV -2.2 mm). Control rats were treated according to the same procedure, and they were inoculated with an equivalent volume of artificial cerebrospinal fluid.
PEA (10mg/kg) was i.p. administered for 7 consecutive days starting from the day of surgery.
After 24h from the last administration, rats were sacrificed by decapitation or transcardiac perfusion. Obtained brains were processed for western blot and immunofluorescence analyses.
In order to test the effect of PEA on Aβ-induced astrogliosis, we explored the expression of GFAP and S100B, specific markers of astrocyte activity. We observed a marked increase in both GFAP and S100B expression after Aβ challenge. This enhancement was significantly attenuated by PEA treatment.
Another set of experiments was aimed at assessing the effect of PEA on the production of inflammatory factors induced by Aβ. Peptide injection resulted in a significant increase in iNOS and COX-2 expression. Such protein increase paralleled pro-inflammatory cytokines up-release, such as IL1β and TNFα. Also in this case PEA antagonized the enhancement of both expression and release of all pro-inflammatory molecules detected.
In conclusion, the current study suggests the ability of PEA to mitigate astrocyte activation and neuroinflammatory process in an in vivo model of AD.
The relevance of these results resides in the hypothesis that pharmacological attenuation of excessive and prolonged reactive gliosis may serve as innovative strategies for therapies aimed at antagonizing the course of AD.
[1] Glass et al. Cell. 2010; 140: 918-34
[2] Craft et al. Glia. 2006; 53: 484–90
[3] Wyss-Coray and Mucke. Neuron. 2002; 35: 419-32
[4] Mackie and Stella. AAPS J. 2006; 8: E298-306
[5] Scuderi et al. J Cell Mol Med. 2011 Jan 21. doi: 10.1111/j.1582-4934.2011.01267.x.