Nathalie Savedra Gomes

Indoleamine-2,3-dioxygenase mediates neurobehavioral alterations induced by an intracerebroventricular injection of amyloid-β1-42 peptide in mice.

Alzheimers disease (AD) is a neurodegenerative disorder that is characterized by a progressive cognitive decline along with various neuropsychiatric symptoms, including depression and anxiety. Increasing evidence has been proposed the activation of the tryptophan-degrading indoleamine-2,3-dyoxigenase (IDO), the rate-limiting enzyme of kynurerine pathway (KP), as a pathogenic factor of amyloid-beta (Aβ)-related inflammation in AD. In the current study, the effects of an intracerebroventricular (i.c.v.) injection of Aβ1-42 peptide (400pmol/mice; 3μl/site) on the regulation of KP biomarkers (IDO activity, tryptophan and kynurerine levels) and the impact of Aβ1-42 on neurotrophic factors levels were investigated as potential mechanisms linking neuroinflammation to cognitive/emotional disturbances in mice. Our results demonstrated that Aβ1-42 induced memory impairment in the object recognition test. Aβ1-42 also induced emotional alterations, such as depressive and anxiety-like behaviors, as evaluated in the tail suspension and elevated-plus maze tests, respectively. We observed an increase in levels of proinflammatory cytokines in the Aβ1-42-treated mice, which led to an increase in IDO activity in the prefrontal cortex (PFC) and the hippocampus (HC). The IDO activation subsequently increased kynurerine production and the kynurenine/tryptophan ratio and decreased the levels of neurotrophic factors in the PFC and HC, which contributed to Aβ-associated behavioral disturbances. The inhibition of IDO activation by IDO inhibitor 1-methyltryptophan (1-MT), prevented the development of behavioral and neurochemical alterations. These data demonstrate that brain IDO activation plays a key role in mediating the memory and emotional disturbances in an experimental model based on Aβ-induced neuroinflammation.

Hesperidin reverses cognitive and depressive disturbances induced by olfactory bulbectomy in mice by modulating hippocampal neurotrophins and cytokine levels and acetylcholinesterase activity

Depression is a serious mental disorder that is becoming more common. To better treat patients suffering from this illness, elucidation of the underlying psychopathological and neurobiological mechanisms of depression is needed. Based on the evidence, we sought to investigate the effects of hesperidin in a model of depression induced by olfactory bulbectomy (OB). C57BL/6 mice were treated with hesperidin (50mg/kg) and imipramine (10mg/kg, positive control) after OB induction. The brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), interleukin 1β (IL-1β) and interleukin 6 (IL-6) levels and acetylcholinesterase activity were analyzed in the hippocampus of the mice. The behavioral parameters were also verified in the model of depression induced by OB. This study demonstrated that OB increased the pro-inflammatory cytokines levels and acetylcholinesterase activity in the hippocampus, exploratory activity in the open field test and immobility in the forced swimming test in mice. In addition, OB decreased the BDNF and NGF levels in the hippocampus, grooming time in the splash test and memory consolidation in the Morris water maze task. Treatment with hesperidin, similar to imipramine, was effective in preventing these behavioral and neurochemical alterations. We suggest that the main targets of hesperidin are pro-inflammatory cytokine modulation, helping to maintain brain plasticity and acetylcholinesterase activity regulation, which are closely linked with antidepressant-like action, as shown by behavior tests. This study demonstrated that there is a pharmacological effect of hesperidin in alterations induced by OB in mice, indicating that hesperidin could be useful as a treatment for depression.

Aging exacerbates cognitive and anxiety alterations induced by an intracerebroventricular injection of amyloid-β 1–42 peptide in mice

&NA; An increasing body of evidence indicates that the activation of indoleamine‐2,3‐dyoxigenase (IDO), a first and rate‐limiting enzyme in the kynurenine (KYN) pathway, is involved in A&bgr;1–42‐neurotoxicity and AD pathogenesis. We have reported for the first time that brain IDO activation is related to A&bgr;1–42 exposure in young mice. Because aging is characterized by a brain dyshomeostasis and because it remains the most dominant risk factor for AD, the purpose of this study was to determine whether aging is associated with a higher sensitivity to behavioural and neurochemical alterations elicited by an intracerebroventricular (i.c.v.) injection of A&bgr;1–42 (400 pmol/mice), and whether KYN pathway is involved in these effects. We confirmed that aged mice displayed higher cognitive deficit in the object recognition test and higher anxiety‐like behaviour in the elevated plus‐maze and open field tests after the A&bgr;1–42 administration. Aged mice also responded to A&bgr;1–42 with a higher deficiency of brain‐derived neurotrophic factor, glutathione levels and total radical‐trapping antioxidant capacity, a higher IDO activity, and a higher KYN and KYN/tryptophan ratio in the prefrontal cortex and hippocampus. These effects of A&bgr;1–42 were associated with a higher proinflammatory status, as measured by higher levels of interleukin‐6, lower levels of interleukin‐10 and higher expression of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (Iba1) in the brain of aged mice. These results represent primary evidence suggesting that age‐associated inflammatory signature and down‐regulation of neuroprotectants in the brain render aged mice more vulnerable to A&bgr;1–42‐induced memory loss, anxiety symptoms and KYN pathway dysregulation. HighlightsIndoleamine‐2,3‐dioxigenase mediates behavioural disturbances induced by A&bgr;1–42.Aging exacerbates A&bgr;1–42‐induced cognitive and anxiety deficits.Aging aggravates A&bgr;1–42‐mediated neuroinflammation.Aging aggravates BDNF and antioxidant deficiency elicited by A&bgr;1–42.Aging further increase KYN dysregulation in brain of A&bgr;1–42‐treated mice.