The intricate interplay between the gut and the brain has gained increasing attention in elucidating the pathophysiology of neuropsychiatric disorders. Within this complex network, the endocannabinoid system (ECS) emerges as a key regulator of multiple physiological functions both at the intestinal and brain level modulating stress response and neuroinflammation, interconnected processes involved in most neurological disorders. The ECS comprises the receptors CB1 and CB2, the endogenous cannabinoids N-arachidonoyl-ethanolamine (AEA), and 2-arachidonoyl-glycerol (2-AG), and the enzymes responsible for their synthesis and degradation: N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) and fatty-acid amide hydrolase 1 (FAAH) for AEA, and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) for 2-AG. Inflammation is known to impact on the equilibrium between the brain and the gut: molecular alterations induced by an immune activation, like a systemic administration of lipopolysaccharide (LPS), reverberates from the periphery to the CNS, leading to neuroinflammation. Environmental enrichment, which encompasses diverse sensorimotor stimuli and social interactions, has been shown to promote neuroplasticity and cognitive and emotional well-being, reducing inflammation, mitigating stress, and improving gastrointestinal motility and function. The objective of this study was twofold: 1) investigate whether the quality of the living environment could influence the ECS and 2) explore the potential role of ECS in mediating the impact of the environment on the gut-brain response induced by a systemic administration of LPS. Methods: Male C57BL6J mice (13 weeks-old) were randomly housed in an Impoverished (IE) or Enriched (EE) Environment condition for 28 days, then received either LPS (0.830 mg/Kg, i.p.) or saline (SAL) and were sacrificed 24h later. Hippocampus (HIPP) and proximal colon (PC) were dissected, gene expression and metabolomic analysis were carried out by qRT-PCR and HPLC-MS/MS, respectively. Results: Mice who experienced EE-housing showed a significant downregulation of the gene expression of CB2 receptors in both HIPP and PC regardless of the treatment. Environment differently affected both the AEA and 2-AG levels and the gene expression of their metabolic enzymes in the two examined areas of SAL-treated animals, while a specific effect in attenuating the LPS-induced decrease of 2-AG levels and of DAGL and MAGL expression was observed only in the PC of EE-housed animals. Conclusion: These results underscore the role of the environmental quality in modulating the ECS signalling and the effects of environment in influencing the neuroinflammatory response suggesting a potential role of ECS in mediating the environmental implications on the gut-brain interactions. Our findings offer new insights for novel possible pharmacological interventions for neuropsychiatric disorders targeting both gut and brain domains.

Environmental quality modulates the endocannabinoid system along the gut-brain axis in a mouse model of LPS-induced neuroinflammation / Rigillo, G; Benatti, C; Toscano, Y; Ciani, M; Rivi, V; Imbeni, F; Pani, L; Blom, Johanna Maria Catharina; Brunello, N; Alboni, S; Tascedda, F. - (2024). (Intervento presentato al convegno 42° Congresso Nazionale della Società Italina di Farmacologia “Science today for a better medicine tomorrow" tenutosi a Sorrento nel 13-16 Novembre).

Environmental quality modulates the endocannabinoid system along the gut-brain axis in a mouse model of LPS-induced neuroinflammation

G Rigillo
;
C Benatti;Toscano Y;M Ciani;V Rivi;F Imbeni;L Pani;Blom;N Brunello;S Alboni;F Tascedda
2024

Abstract

The intricate interplay between the gut and the brain has gained increasing attention in elucidating the pathophysiology of neuropsychiatric disorders. Within this complex network, the endocannabinoid system (ECS) emerges as a key regulator of multiple physiological functions both at the intestinal and brain level modulating stress response and neuroinflammation, interconnected processes involved in most neurological disorders. The ECS comprises the receptors CB1 and CB2, the endogenous cannabinoids N-arachidonoyl-ethanolamine (AEA), and 2-arachidonoyl-glycerol (2-AG), and the enzymes responsible for their synthesis and degradation: N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD) and fatty-acid amide hydrolase 1 (FAAH) for AEA, and diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) for 2-AG. Inflammation is known to impact on the equilibrium between the brain and the gut: molecular alterations induced by an immune activation, like a systemic administration of lipopolysaccharide (LPS), reverberates from the periphery to the CNS, leading to neuroinflammation. Environmental enrichment, which encompasses diverse sensorimotor stimuli and social interactions, has been shown to promote neuroplasticity and cognitive and emotional well-being, reducing inflammation, mitigating stress, and improving gastrointestinal motility and function. The objective of this study was twofold: 1) investigate whether the quality of the living environment could influence the ECS and 2) explore the potential role of ECS in mediating the impact of the environment on the gut-brain response induced by a systemic administration of LPS. Methods: Male C57BL6J mice (13 weeks-old) were randomly housed in an Impoverished (IE) or Enriched (EE) Environment condition for 28 days, then received either LPS (0.830 mg/Kg, i.p.) or saline (SAL) and were sacrificed 24h later. Hippocampus (HIPP) and proximal colon (PC) were dissected, gene expression and metabolomic analysis were carried out by qRT-PCR and HPLC-MS/MS, respectively. Results: Mice who experienced EE-housing showed a significant downregulation of the gene expression of CB2 receptors in both HIPP and PC regardless of the treatment. Environment differently affected both the AEA and 2-AG levels and the gene expression of their metabolic enzymes in the two examined areas of SAL-treated animals, while a specific effect in attenuating the LPS-induced decrease of 2-AG levels and of DAGL and MAGL expression was observed only in the PC of EE-housed animals. Conclusion: These results underscore the role of the environmental quality in modulating the ECS signalling and the effects of environment in influencing the neuroinflammatory response suggesting a potential role of ECS in mediating the environmental implications on the gut-brain interactions. Our findings offer new insights for novel possible pharmacological interventions for neuropsychiatric disorders targeting both gut and brain domains.
2024
42° Congresso Nazionale della Società Italina di Farmacologia “Science today for a better medicine tomorrow"
Sorrento
13-16 Novembre
Rigillo, G; Benatti, C; Toscano, Y; Ciani, M; Rivi, V; Imbeni, F; Pani, L; Blom, Johanna Maria Catharina; Brunello, N; Alboni, S; Tascedda, F
Environmental quality modulates the endocannabinoid system along the gut-brain axis in a mouse model of LPS-induced neuroinflammation / Rigillo, G; Benatti, C; Toscano, Y; Ciani, M; Rivi, V; Imbeni, F; Pani, L; Blom, Johanna Maria Catharina; Brunello, N; Alboni, S; Tascedda, F. - (2024). (Intervento presentato al convegno 42° Congresso Nazionale della Società Italina di Farmacologia “Science today for a better medicine tomorrow" tenutosi a Sorrento nel 13-16 Novembre).
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