Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology最新文献

Neuroinflammation affects patients with major depressive disorder and is linked to severe, treatment-resistant symptoms, making it a promising therapeutic target for improving depressive symptoms. This study highlighted the neuroprotective role of pentoxifylline (PTX) against lipopolysaccharide (LPS)-induced neuroinflammation and associated behavioral deficits. Mice were injected with LPS (1 mg/kg, i.p) to induce neuroinflammation and treated with PTX (10 mg/kg, i.p). Behavioral and biochemical analyses were performed to evaluate depressive-like behaviors and examine hippocampal protein expression associated with neuroinflammation and synaptic plasticity. LPS administration increased proinflammatory cytokine production (IL-1, IL6, and TNF-α), microglial activation (IBA-1/GFAP), and dysregulation of key synaptic proteins, including BDNF and TrkB, in the hippocampus of mice. Concomitantly, LPS reduced Phosphatase and tensin homolog (PTEN) phosphorylation, potentially contributing to increased neuroinflammation. PTX treatment effectively attenuated LPS-induced effects by suppressing inflammatory responses, restoring BDNF/TrkB signaling, and rescuing synaptic impairments. Mechanistically, PTX treatment increased PTEN phosphorylation and was reversed by the TrkB inhibitor K252a, suggesting that PTX upregulates TrkB/BDNF signaling, leading to increased PTEN phosphorylation and subsequent inhibition of PTEN activity. These findings highlight the potential of PTX as a therapeutic agent for neuroinflammatory conditions, possibly exerting its effects by modulating the PTEN/TrkB/BDNF signaling axis and suggest a novel mechanism of action involving the modulation of the PTEN/TrkB/BDNF signaling pathway.

Dapagliflozin, an approved SGLT2 inhibitor, has been shown to have extra-glycemic effects like cardio-reno protection. However, the neuroprotective effects of SGLT2 inhibitors against diabetic neuropathy (DN) have not been explored. The current study aimed to determine the neuroprotective potential of Dapagliflozin against STZ-NAD-induced DN in Wistar rats via IGF-1 signaling. DN was induced by STZ-NAD in male Wistar rats. After 60 days of induction, behavioural tests were conducted to access DN, and treatment with Dapagliflozin (0.75 mg/kg & 1.50 mg/kg) was initiated for 30 days. At the end of the study, the brain and sciatic nerve were isolated and expression analysis of IGF-1R signaling molecules was carried out using western blotting, qRTPCR, and immunohistochemistry. Structural changes in the brain and sciatic nerve were ascertained by histopathology. The results showed that treatment with Dapagliflozin improved behavioural parameters in STZ-NAD-induced DN rats. The decreased expression levels of IGF1R signaling pathway molecules and increased expression of p-AKT were found to increase and decrease in the brain and sciatic nerve, respectively after the treatment. Histological studies demonstrated the restoration of normal architecture of the brain and sciatic nerve after treatment with dapagliflozin. The altered expression of IGF-1R signaling molecules established the neuroprotective potential of dapagliflozin against DN.

Migraine is a prevalent neurological disorder characterized by severe, recurrent headaches accompanied by symptoms, such as nausea, photophobia, and phonophobia, significantly affecting the quality of life of millions of people worldwide. Although the neurovascular pathway, involving blood vessel dilation and neurogenic inflammation, has been a cornerstone in understanding migraine pathophysiology. Emerging evidence suggests that immune dysregulation plays a pivotal role in the onset and progression of migraine. This review uniquely synthesizes recent advances linking immune regulatory pathways to migraine, an area that has not been widely explored in the literature. Specifically, we highlighted the involvement of CD4 + CD25 + regulatory T (Treg) cells, interleukins, and pro-inflammatory and anti-inflammatory cytokines, which have been implicated in pain signaling and immune imbalance in patients with migraine. Furthermore, genetic studies have provided compelling evidence by identifying associations between migraine susceptibility and immune-related polymorphisms, particularly in forkhead box P3 (FOXP3) and nuclear factor of activated T cells (NFAT). Moreover, the higher prevalence of migraine in individuals with comorbid autoimmune diseases further supports the hypothesis of a shared pathophysiological mechanism. Despite the growing recognition of immune involvement in migraine, its precise mechanisms remain unclear. By integrating key immune biomarkers and genetic insights, this review proposes a novel framework for understanding the immune-mediated pathways in migraine progression. Future research should focus on elucidating the specific immunological mechanisms underlying migraine, which could open new avenues for innovative, targeted therapeutic strategies.

Proinflammatory cytokines, especially interleukin-17 A (IL-17 A) have been found to be significantly associated with AD patients. IL-17 A amplifies neuroinflammation during AD pathology. This study highlighted the ability of IL-17 A to exacerbate amyloid-beta-induced pathology in animals. The AD pathology was induced with repeated intranasal administration of Aβ along with recombinant mouse IL-17 A (rmIL-17) at 1, 2 and 4 µg/kg for seven alternate days. Although, the combination of rmIL-17 and Aβ did not have severe effects on memory of the animals, but it drastically increased the IL-17 A mediated signaling, level of proinflammatory cytokines, oxidative stress and reduced antioxidants in the hippocampus and cortex regions of the animal brains. Interestingly, combining rmIL-17 with Aβ also triggered the expression of AD structural markers like pTau, amyloid-beta and BACE1 in the brain regions. Furthermore, rmIL-17 with Aβ exposure stimulated astrocytes and microglia leading to activation of proinflammatory signaling in the brain of the animals. These results showed the propensity of IL-17 A to promote severity of AD pathology and suggest IL-17 A as potent therapeutic target to control AD progression.

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition affecting cognitive and social functions all over childhood. Monosodium glutamate (MSG) is a common food additive associated with ADHD-like symptoms in children. Nutraceuticals, like sesamol (SE) and astaxanthin (AST), or physical activity (PHA) were reported to possess beneficial effects on human health. Meanwhile, still their neuroprotective effect against ADHD has been poorly investigated. This study aimed to investigate the impact of SE, AST and PHA either separately or combined on ADHD-like behaviors induced by MSG in rat pups. Eighty-four male Sprague Dawley rat pups were randomly allocated into seven groups; control, MSG, (PHA + MSG), (SE + MSG), (AST + MSG), (SE + AST + MSG), and (COMB [PHA + SE + AST] + MSG) and treated for eight weeks. MSG-induced ADHD-like behavior was evaluated, via assessing behavioral outcomes; neurotransmitters' levels; five pathway biomarkers, coupled with histopathological and immunohistochemical studies. Rats exposed to PHA or treated with SE or AST either separately or combined exhibited enhanced attention, locomotor, and cognitive abilities, compared to MSG-intoxicated group. All treatments remarkably improved MSG-induced abnormalities in neurotransmitters' levels; biochemical markers; along with histological findings, via modulating HMGB1/RAGE/JAK-2/STAT-3, PI3K/AKT/CREB/BDNF, AMPK/SIRT-1 and PERK/CHOP pathways. Nevertheless, the combination of PHA with nutraceuticals (SE and AST) elicited more favorable effects in all measured parameters and histological findings, compared to other treated groups. In conclusion, this study revealed the superiority of the combination of nutraceuticals with PHA, over other standalone treatments, in amelioration of MSG-induced ADHD-like behaviors in rat pups, via fine-tuning of HMGB1/RAGE, PI3K/AKT/CREB/BDNF, AMPK/SIRT-1 and PERK/CHOP pathways.

Renal ischemia-reperfusion (RIR) induces brain damage as a distant organ. Oleuropein has antioxidant properties. This study aimed to explore oleuropein's protective effects against brain injury following RIR in rats. Thirty-six male Wistar rats were divided into six groups (n = 6) including sham, oleuropein (200 mg/kg), RIR, and RIR groups treated with oleuropein (50, 100, and 200 mg/kg). 48 h after injury, blood urea nitrogen (BUN) and creatinine levels were surveyed. The western blotting analysis was performed to assay the interleukin-1 beta (IL-1β), IL-10, tumor necrosis factor-alpha (TNF-α), and nuclear factor kappa-light-chain-enhancer of activated B cells p65 (NF-κB p65), Bcl-2 associated X protein (Bax), B-cell lymphoma-2 (Bcl-2), cleaved caspase-3, glutathione peroxidase-4 (GPX4), nuclear factor erythroid-related factor-2 (NRF2), solute carrier family 7, member 11 (SLC7A11), and anti-acyl-CoA synthetase long-chain family 4 (ACSL4) proteins in kidney and/or brain tissues. Also, malondialdehyde (MDA) and total antioxidant capacity (TAC) levels, the activity of GPx, catalase, and superoxide dismutase (SOD) were evaluated. Kidney and brain tissues damage scores (KTDS and BTDS) were determined by H&E staining method. Prussian blue staining was conducted to identify iron accumulation. RIR significantly increased BUN, serum creatinine levels, KTDS, BTDS, iron deposition, MDA concentration, Bax, cleaved caspase-3, IL-1β, TNF-α, NF-κB p65, ACSL4 proteins expression levels, while decreasing TAC content, SOD, GPx, and catalase activity, Bcl-2, GPX4, SLC7A11 and NRF2 proteins expression in kidney and/or brain tissue of RIR group versus the sham (P < 0.05). Moreover, oleuropein attenuated these indicators in the RIR + oleuropein (200 mg/kg) group versus the RIR group (P < 0.05). Our study showed that RIR induced brain damage, and oleuropein exhibited protective effects against brain injury induced by RIR, through inhibiting oxidative stress, inflammation, ferroptosis, and apoptosis mechanisms.

Most current information about neurological disorders and diseases is derived from direct patient and animal studies. However, patient studies in many cases do not allow replication of the early stages of the disease and, therefore, offer limited opportunities to understand disease progression. On the other hand, although the use of animal models allows us to study the mechanisms of the disease, they present significant limitations in developing drugs for humans. Recently, 3D-cultured in vitro models derived from human pluripotent stem cells have surfaced as a promising system. They offer the potential to connect findings from patient studies with those from animal models. In this comprehensive review, we discuss their application in modeling neurodevelopmental conditions such as Down Syndrome or Autism, neurodegenerative diseases such as Alzheimer's or Parkinson's, and viral diseases like Zika virus or HIV. Furthermore, we will discuss the different models used to study prenatal exposure to drugs of abuse, as well as the limitations and challenges that must be met to transform the landscape of research on human brain disorders.