Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and alteration of other non-cognitive domains. Novel epidemiological data globally recognized the AD as the leading cause of dementia as well as one of the main causes of death. Overwhelming evidence showed the primary role for the modulation of the endocannabinoid system in the pathogenesis of AD. To this regard, several studies highlighted the neuroprotective and anti-inflammatory effects associated to the increased tone of acylethanolamides, which could be potentially used as a novel therapeutic strategy for neurodegenerative disorders, such as AD. The pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH) can increase the endogenous tone of acylethanolamides, such as anandamide. Currently, it is well known that anandamide increase is able to produce cognitive improvements, as well as anxiolytic- and antidepressant-like effects in rodents. Nevertheless, the phase I clinical trial with BIA 10–2474, a non-selective FAAH inhibitor, has been discontinued due to its off-target effects, which caused severe adverse effects. Therefore, in our project we tested the hypothesis that a chronic treatment with the highly selective FAAH inhibitor PF-3845 (Ki = 0.23 μM) could exert beneficial effects on the onset and/or the progression of the neurofunctional alterations found in the triple transgenic mouse model of AD (3×Tg-AD). 3×Tg-AD mice develop a progressive and age-related neuropathology characterized by cognitive decline and depressive-like symptoms associated to amyloid-β and tau pathology. This complex phenotype starts appearing around 5-6 months of age and is fully expressed during the old age (10 to 12 months). To this aim, both young (“pre-symptomatic” at 4 months of age) and old (“symptomatic” at 10 months of age) male 3×Tg-AD mice were treated every other day with PF-3845 (10 mg/kg, s.c.) or vehicle (saline, tween80 and PEG, 2 ml/kg, s.c.) for two months. At the end of the treatments, we tested our hypothesis following an integrated approach, involving behavioural (tests for cognitive and depressive-like alterations), biochemical and immunohistochemical analyses (for the neuropathological markers and BDNF analyses), as well as neurochemical evaluation (HPLC analysis of monoamine levels). As expected, PF-3845 treatment was able to improve spatial and recognition memory, and to ameliorate the depressive-like symptoms in both young and old 3×Tg-AD mice. Moreover, PF-3845 treatment (i) reduced Aβ and tau pathology in the frontal cortex and hippocampus, (ii) increased the hippocampal expression of BDNF and (iii) modulated the monoamine levels in both brain regions. Overall, PF-3845 treatment was efficacious not only in preventing the onset of the neurofunctional alterations, but also to partially restore these alterations in old symptomatic mice, thus suggesting that the selective FAAH inhibition may still represent a promising target for the development of novel and efficacious anti-Alzheimer’s therapies.
The selective inhibition of FAAH ameliorates cognitive decline, depressive-like symptoms and neurophatological alterations in a murine model of Alzheimer's disease / Calcagnini, Silvio; Bedse, Gaurav; Lavecchia, ANGELO MICHELE; Caruso, Alessandra; Scaccianoce, Sergio; DE CEGLIA, Marialuisa; Gallelli, CRISTINA ANNA; Romano, Adele; Cassano, Tommaso; Gaetani, Silvana. - (2018). (Intervento presentato al convegno 28th Annual International Cannabinoid Research Society Symposium on the Cannabinoids, ICRS-2018 tenutosi a Leiden (Olanda)).
The selective inhibition of FAAH ameliorates cognitive decline, depressive-like symptoms and neurophatological alterations in a murine model of Alzheimer's disease
Calcagnini SilvioPrimo
;Bedse gauravSecondo
;Lavecchia Angelo Michele;Caruso Alessandra;Scaccianoce Sergio;de Ceglia Marialuisa;GALLELLI, CRISTINA ANNA;Gaetani SilvanaUltimo
2018
Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and alteration of other non-cognitive domains. Novel epidemiological data globally recognized the AD as the leading cause of dementia as well as one of the main causes of death. Overwhelming evidence showed the primary role for the modulation of the endocannabinoid system in the pathogenesis of AD. To this regard, several studies highlighted the neuroprotective and anti-inflammatory effects associated to the increased tone of acylethanolamides, which could be potentially used as a novel therapeutic strategy for neurodegenerative disorders, such as AD. The pharmacological inhibition of the enzyme fatty acid amide hydrolase (FAAH) can increase the endogenous tone of acylethanolamides, such as anandamide. Currently, it is well known that anandamide increase is able to produce cognitive improvements, as well as anxiolytic- and antidepressant-like effects in rodents. Nevertheless, the phase I clinical trial with BIA 10–2474, a non-selective FAAH inhibitor, has been discontinued due to its off-target effects, which caused severe adverse effects. Therefore, in our project we tested the hypothesis that a chronic treatment with the highly selective FAAH inhibitor PF-3845 (Ki = 0.23 μM) could exert beneficial effects on the onset and/or the progression of the neurofunctional alterations found in the triple transgenic mouse model of AD (3×Tg-AD). 3×Tg-AD mice develop a progressive and age-related neuropathology characterized by cognitive decline and depressive-like symptoms associated to amyloid-β and tau pathology. This complex phenotype starts appearing around 5-6 months of age and is fully expressed during the old age (10 to 12 months). To this aim, both young (“pre-symptomatic” at 4 months of age) and old (“symptomatic” at 10 months of age) male 3×Tg-AD mice were treated every other day with PF-3845 (10 mg/kg, s.c.) or vehicle (saline, tween80 and PEG, 2 ml/kg, s.c.) for two months. At the end of the treatments, we tested our hypothesis following an integrated approach, involving behavioural (tests for cognitive and depressive-like alterations), biochemical and immunohistochemical analyses (for the neuropathological markers and BDNF analyses), as well as neurochemical evaluation (HPLC analysis of monoamine levels). As expected, PF-3845 treatment was able to improve spatial and recognition memory, and to ameliorate the depressive-like symptoms in both young and old 3×Tg-AD mice. Moreover, PF-3845 treatment (i) reduced Aβ and tau pathology in the frontal cortex and hippocampus, (ii) increased the hippocampal expression of BDNF and (iii) modulated the monoamine levels in both brain regions. Overall, PF-3845 treatment was efficacious not only in preventing the onset of the neurofunctional alterations, but also to partially restore these alterations in old symptomatic mice, thus suggesting that the selective FAAH inhibition may still represent a promising target for the development of novel and efficacious anti-Alzheimer’s therapies.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.