Neuroinflammation, neurodegeneration and alteration of spatial memory in BALB/c mice through ampicillin-induced gut dysbiosis; NOS2 and NFL involvement in a microbiota-gut-brain axis model.

We aimed to investigate ampicillin (AMP) mechanisms in microbiota-gut-brain axis. We evaluated its effect on two gut and brain regions and behavioral performances. We administred AMP (1 g/l) to BALB/c mice for 21 days. Then, we analyzed body weigth change, stool consistency scoring, gut length, intestinal microbiota composition, nitric oxide synthase 2 (NOS2) expression and tissue integrity. We subsequently evaluated NOS2, GFAP, CD68 and NFL cerebral expression and spatial memory.Interestingly, our data showed gut microbiota disruption, NOS2 upregulation and tissue damage, associated to cerebral NOS2, GFAP, CD68 and NFL over-expression and behavioral alteration. Antiobiotic therapy should be prescribed with great caution.

Cardamonin inhibits pro-inflammatory cytokine production and suppresses NO pathway in PBMCs from patients with primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder with a complex pathophysiology primarily affecting exocrine glands, leading to compromised secretory function. Recent studies imply that many inflammatory mediators, such as pro-inflammatory cytokines and nitric oxide, are critical in the development and perpetuation of pSS systemic manifestations. In the current study, we aimed to investigate the ex vivo immunomodulatory effect of cardamonin (C16H14O4), on pro-inflammatory cytokines, TNF-α, IL-6 and inducible nitric oxide synthase (iNOS) expression during pSS. For this purpose, peripheral blood mononuclear cells isolated from pSS patients and healthy controls were cultured with different concentrations of cardamonin. Cytokine levels were measured by ELISA and NO production was assessed using the Griess method. Inducible nitric oxide synthase expression and NF-κB activity were analyzed by immunofluorescence staining. Our results suggest that cardamonin inhibits TNF-α, IL-6 and NO production and downregulates iNOS expression and NF-κB activation. Collectively, our results highlight the ex vivo immunomodulatory effects of cardamonin on pro-inflammatory cytokine production and NO pathway in pSS patients. Therefore, cardamonin is a potential candidate for controlling inflammation during pSS.

All-trans retinoic acid (ATRA) prevents lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment in aged rats.

We aimed to investigate preventive effects of All-trans retinoic acid (ATRA) on a lipopolysaccharide (LPS)-induced aged neuroinflammation model. We analyzed behavior, systemic nitric oxide (NO) production, cerebral NO synthase (NOS2) and ß-amyloid (Aß) 1-42 expression and tissue integrity in the neuroinflammation model pretreated with ATRA (150µg/ml/rat/day) for 30days. Our results showed that LPS treatment (500µg/kg/day) for 7days disturbed memory, enhanced systemic NO production, NOS2 and Aß 1-42 cerebral expression and generated an Alzheimer's disease (AD)-like neuronal degeneration. Interestingly, ATRA pretreatment prevented the LPS-induced deleterious effects. ATRA could be a potent preventive approach in AD.

All-trans-retinoic acid modulates nitric oxide and interleukin-17A production by peripheral blood mononuclear cells from patients with Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD), the most common form of dementia in the elderly, is a neurodegenerative disorder associated with a complex pathophysiology. It is accepted that inflammation contributes to the pathogenesis of AD. All-trans-retinoic acid (ATRA) is a bioactive derivative of vitamin A that has shown immunomodulatory effects in many immune disorders. OBJECTIVES: In our study, we aimed to investigate in vitro immunomodulatory effects of ATRA on inducible nitric oxide synthase (iNOS) expression and interleukin-17A production during AD. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from 30 Algerian AD patients and 14 age-matched nondemented controls were treated (or not) with ATRA. Production of NO and IL-17A in culture media was measured by the modified Griess method and enzyme-linked immunosorbent assay, respectively. Expression of iNOS in PBMCs was examined by fluorescence immunostaining. RESULTS: Our results showed higher spontaneous in vitro production of NO related to overexpression of iNOS in AD patients compared to controls. Remarkably, ATRA treatment showed an important downregulatory effect on NO production and iNOS expression in patients. This effect was associated with a reduction in IL-17A production and increased IL-10 release. CONCLUSIONS: Taken together, our results indicate that ATRA exerts anti-inflammatory effects in AD. Furthermore, ATRA represents a promising tool for monitoring inflammatory responses associated with disease progression.

IFN-γ and TNF-α are involved during Alzheimer disease progression and correlate with nitric oxide production: a study in Algerian patients.

Alzheimer's disease (AD) is a neurodegenerative disease leading to a progressive and irreversible loss of mental functions. It is characterized by 3 stages according to the evolution and the severity of the symptoms. This disease is associated with an immune disorder, which appears with significant rise in the inflammatory cytokines and increased production of free radicals such as nitric oxide (NO). Our study aims to investigate interferon (IFN)-γ and tumor necrosis factor-α (TNF-α) involvement in NO production, in vivo and ex vivo, in peripheral blood mononuclear cells from Algerian patients (n=25), according to the different stages of the disease (mild Alzheimer's, moderate Alzheimer's, and severe Alzheimer's) in comparison to mild cognitive impairment (MCI) patients. Interestingly, we observed that in vivo IFN-γ and TNF-α levels assessed in patients with AD in mild and severe stages, respectively, are higher than those observed in patients with moderate stage and MCI. Our in vivo and ex vivo results show that NO production is related to the increased levels of IFN-γ and TNF-α, in mild and severe stages of AD. Remarkably, significant IFN-γ level is only detected in mild stage of AD. Our study suggests that NO production is IFN-γ dependent both in MCI and mild Alzheimer's patients. Further, high levels of NO are associated with an elevation of TNF-α levels in severe stage of AD. Collectively, our data indicate that the proinflammatory cytokine production seems, in part, to be involved in neurological deleterious effects observed during the development of AD through NO pathway.