In vivo imaging of neuroinflammation

We briefly outline the rationale for employing positron emission tomography (PET), using the ligand [¹¹C](R)-PK11195, the binding site for which is highly expressed by activated microglia, in order (a) to detect in vivo neuroinflammatory changes occurring in a variety of brain diseases and at different disease stages and (b) to monitor the progression of neuroinflammation as a generic in vivo marker of ‘disease activity’. The use of [¹¹C](R)-PK11195 PET is described as a systematic attempt at measuring the emerging phenomenology of tissue pathology itself—as opposed to measuring, for example, the loss of neuronal function or structure—and as a proof of principle for the clinical utility of imaging glial cells in vivo.     

Synthesis and biological evaluation of novel flavanone derivatives as potential antipsychotic agents

In this study, a series of novel flavanone derivatives were designed and synthesized, and the antipsychotic activities of the target compounds were evaluated in vitro and in vivo. The results showed that synthesized compounds 7a – 7g decreased the activity of dopamine D₂ receptors in HEK293 cells co‐transfected with D₂ receptor/G protein α16a, with IC₅₀ values of 0.051–0.35 μm . Compounds 7a – 7g inhibited the over‐production of nitric oxide stimulated by lipopolysaccharide/interferon‐γ in BV‐2 microglial cells. In mice, intragastric administration of 7d , 7e , and 7g reversed the increase in locomotor activity induced by MK‐801 (an antagonist of NMDA receptors) and decreased the hyperactivity of climbing behavior induced by apomorphine (a dopamine receptor agonist). These results suggest that some of the novel flavanone derivatives have potential antipsychotic effects and may be useful in the treatment of schizophrenia.     

Hazelnut and neuroprotection: Improved memory and hindered anxiety in response to intra-hippocampal Aβ injection

Objectives: Corylus avellana L. (hazelnut) is known to be a delicious and nutritious food. This study was carried out to evaluate the use of hazelnut as a therapy for memory impairment because in Iranian traditional medicine, it is recommended for those suffering from a particular type of dementia, with symptoms of Alzheimer's disease.

Methods: In this study, rats were fed with hazelnut kernel [(without skin) 800?mg/kg/day] during 1 week before stereotaxic surgery to 24?hours before behavioral testing (in general, for 16 consecutive days) and the effect of hazelnut eating on memory, anxiety, neuroinflammation and apoptosis was assessed in the amyloid beta-injected rat.

Results: The results of this study showed that feeding with hazelnut improved memory, (which was examined by using Y-maze test and shuttle box apparatus), and reduced anxiety-related behavior, that was evaluated using elevated plus maze. Also, western blotting analysis of cyclooxygenase-2, interleukin-1β, tumor necrosis factor-α, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein, and caspase-3 showed that hazelnut has an ameliorating effect on the neuroinflammation and apoptosis caused by Aβ.

Discussion: These ?ndings suggest that hazelnut, as a dietary supplement, improves healthy aging and could be a beneficial diet for the treatment of AD.     

Microglial toll-like receptors and Alzheimer’s disease

Microglial activation represents an important pathological hallmark of Alzheimer’s disease (AD), and emerging data highlight the involvement of microglial toll-like receptors (TLRs) in the course of AD. TLRs have been observed to exert both beneficial and detrimental effects on AD-related pathologies, and transgenic animal models have provided direct and credible evidence for an association between TLRs and AD. Moreover, analyses of genetic polymorphisms have suggested interactions between genetic polymorphisms in TLRs and AD risk, further supporting the hypothesis that TLRs are involved in AD. In this review, we summarize the key evidence in this field. Future studies should focus on exploring the mechanisms underlying the potential roles of TLRs in AD.     

Decreased motor impulsivity following chronic lithium treatment in male rats is associated with reduced levels of pro-inflammatory cytokines in the orbitofrontal cortex

Lithium’s efficacy in reducing both symptom severity in bipolar disorder (BD) and suicide risk across clinical populations may reflect its ability to reduce impulsivity. Changes in immune markers are associated with BD and suicidality yet their exact role in symptom expression remains unknown. Evidence also suggests that lithium may decrease levels of pro-inflammatory cytokines in the periphery and central nervous system, and that such changes are related to its therapeutic efficacy. However, issues of cause and effect are hard to infer from clinical data alone. Here, we investigated the effects of chronic dietary lithium treatment on rats’ performance of the 5-Choice Serial Reaction Time Task (5CSRTT), a well-validated operant behavioural task measuring aspects of impulsivity, attention and motivation. Male Long-Evans rats received a diet supplemented with 0.3% LiCl (n = 13), or the equivalent control diet (n = 16), during behavioural testing. Blood and brain tissue samples were assayed for a wide range of cytokines once any changes in impulsivity became significant. After 12 weeks, chronic lithium treatment reduced levels of motor impulsivity, as indexed by premature responses in the 5CSRTT; measures of sustained attention and motivation were unaffected. Plasma levels of IL-1β, IL-10 and RANTES (CCL-5) were reduced in lithium-treated rats at this time point. IL-1β, IL-6 and RANTES were also reduced selectively within the orbitofrontal cortex of lithium-treated rats, whereas cytokine levels in the medial prefrontal cortex and nucleus accumbens were comparable with control subjects. These results are consistent with the hypothesis that lithium may improve impulse control deficits in clinical populations by minimising the effects of pro-inflammatory signalling on neuronal activity, particularly within the orbitofrontal cortex.     

Impaired autophagy in microglia aggravates dopaminergic neurodegeneration by regulating NLRP3 inflammasome activation in experimental models of Parkinson’s disease

Microglia-mediated inflammation plays an important role in the pathogenesis of several neurodegenerative diseases including Parkinson’s disease (PD). Recently, autophagy has been linked to the regulation of the inflammatory response. However, the potential role of microglial autophagy in the context of PD pathology has not been characterized. In the present study, we investigated whether impaired microglial autophagy would affect dopaminergic neurodegeneration and neuroinflammation both in vivo and in vitro. In vitro, BV2 microglial cells were exposed to LPS in the presence or absence of autophagy-related gene 5 (Atg5) small interference RNA (Atg5-siRNA). For in vivo study, microglial Atg5 conditional knockout (Atg5^flox/flox; CX3CR1-Cre) mice and their wild-type littermates (Atg5^flox/flox) were intraperitoneally injected with MPTP to induce experimental PD model. Our results revealed that disruption of autophagy by Atg5-siRNA aggravated LPS-induced inflammatory responses in BV2 cells and caused greater apoptosis in SH-SY5Y cells treated with BV2 conditioned medium. In mice, impaired autophagy in microglia exacerbated dopaminergic neuron loss in response to MPTP. The mechanism by which the deficiency of microglial autophagy promoted neuroinflammation and dopaminergic neurodegeneration was related to the regulation of NLRP3 inflammasome activation. These findings demonstrate that impairing microglial autophagy aggravates pro-inflammatory responses to LPS and exacerbates MPTP-induced neurodegeneration by modulating NLRP3 inflammasome responses. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for PD.     

Dopamine D1 receptor agonist A-68930 ameliorates Aβ1-42-induced cognitive impairment and neuroinflammation in mice

Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by progressive cognitive dysfunction and memory impairment. Dopamine is an important catecholaminergic neurotransmitter that controls movement, reward, motivation, and cognition. Recently, dopamine receptors were reported to regulate immune system in both periphery and central nervous system. However, whether dopamine D1 receptor (DRD1) activation could improve neuroinflammation in AD conditions remains unknown. The present study aimed to investigate the therapeutic effects and underlying mechanisms of a potent and selective DRD1 agonist A-68930 on Aβ_1-42-induced mice. Here we showed that intraperitoneal injection of A-68930 significantly ameliorated Aβ_1–42-induced cognitive dysfunction in mice. Moreover, both in vivo and in vitro data showed that A-68930-induced DRD1 activation significantly inhibited NLRP3 inflammasome-dependent neuroinflammation induced by Aβ_1–42, and this effect may be mediated by the activation of AMPK/autophagy signaling pathway, which enhanced NLRP3 inflammasome degradation and thus decreased the secretion of IL-1β and IL-18. The present study suggests that A-68930-induced DRD1 signaling efficiently alleviates Aβ_1–42-induced cognitive impairment and neuroinflammation in mice and BV2 cells, and DRD1 may become a promising therapeutic target for AD.     

Inhibition of protein disulfide isomerase has neuroprotective effects in a mouse model of experimental autoimmune encephalomyelitis

Endoplasmic reticulum (ER) stress is strictly linked to neuroinflammation and involves in the development of neurodegenerative disorders. Protein disulfide isomerase (PDI) is an enzyme that catalyzes formation and isomerization of disulfide bonds and also acts as a chaperone that survives the cells against cell death by removal of misfolded proteins. Our previous work revealed that PDI is explicitly upregulated in response to myelin oligodendrocyte glycoprotein (MOG)-induced ER stress in the brain of experimental autoimmune encephalomyelitis (EAE) mice. The significance of overexpression of PDI in the apoptosis of neural cells prompted us to study the effect of CCF642, efficient inhibitor of PDI, in the recovery of EAE clinical symptoms. Using this in vivo model, we characterized the ability of CCF642 to decrease the expression of ER stress markers and neuroinflammation in the hippocampus of EAE mice. Our observations suggested that CCF642 administration attenuates EAE clinical symptoms and the expression of ER stress-related proteins. Further, it suppressed the inflammatory infiltration of CD4 + T cells and the activation of hippocampus-resident microglia and Th17 cells. We reported here that the inhibition of PDI protected EAE mice against neuronal apoptosis induced by prolonged ER stress and resulted in neuroprotection.