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Background: Apigenin has been reported to exhibit anti-inflammatory and anti-oxidative activities. This study aimed to investigate the protective role of Apigenin on chemotherapy-induced peripheral neuropathy (CIPN). Methods: CIPN mouse model was established using Paclitaxel treatment. Hot plate and tail prick latency tests were performed to examine the allodynia and hyperalgesia behaviors. Antiinflammatory and anti-oxidative effects of Apigenin on CIPN were determined by enzyme-linked immunosorbent (ELISA) assay, Western blot, and qRT-PCR. Nuclear recruitment of nuclear factor erythroid 2-related factor 2 (NRF2) was analyzed to evaluate the underlying mechanisms of the protective effects of Apigenin. Results: Apigenin significantly alleviated CIPN-induced nociceptive behaviors of CIPN mice. It also decreased the TNF-α and IL-1β levels, suppressed oxidative stress and inflammation in the surgical spinal cord tissues. Mechanistically, Apigenin altered the pro-inflammatory and anti-inflammatory phenotypes ratio of microglia through promoting the nuclear recruitment of NRF2 and activating the NRF2/Antioxidant Response Element (ARE) signaling pathway. Conclusions: In summary, Apigenin relieves CIPN by regulating microglia activation and polarization, which provides a potential therapeutic strategy for CIPN treatment. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressive hypokinetic movement disorder caused by selective degeneration of dopaminergic neurons in striatum and dopamine deficiency in a region of the midbrain. LPS is an endotoxin, used as animal model to induce microglial activation, neuroinflammation, oxidative stress, and neurotransmitter alteration with PD-like symptoms. Therefore, to prevent neuroinflammation and neurotransmitter changes and to restore normal brain physiology, we tried apigenin (AGN) alone and in combination with piperine (bioenhancer), in LPS experimental model of rats. In this study, rats were treated with single unilateral intranigral injection of LPS at a dose of 5 μg/5 μl on day 0. The oral administration of AGN (25 and 50 mg/kg; p.o.) alone, AGN (25 mg/kg; p.o.) in combination with piperine (2.5 mg/kg; p.o.), and bromocriptine (10mg/kg; p.o.) started from day 7th once in a day. Intranigral injection of LPS significantly altered body weight and behavioral parameters assessed on weekly basis. Furthermore, the biochemical and neuroinflammatory analysis confirmed (on day 22nd) increased level of nitrite, MDA, SOD, TNF-α, IL-1β, IL-6, and caspase-1, and decreased level of CAT, GSH, and complex-I. Furthermore, altered level of neurotransmitters (DA, GABA, and glutamate) and cellular changes were observed from histopathological and immunohistochemistry (NF-kB and Nrf-2) analysis. Treatment with AGN (25 and 50 mg/kg; p.o.) alone and AGN (25 mg/kg; p.o.) in combination with piperine (2.5 mg/kg; p.o.) significantly attenuated the alteration in body weight, motor impairments, oxidative stress, neuroinflammation, and neurotransmitters in rat brain. The neuroprotective effect of AGN against LPS-induced cell death is attributed by modulating NF-kB and Nrf2 signaling pathway in the striatum. [ABSTRACT FROM AUTHOR]

Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD+) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+, suppressed cuprizone-induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD+ on lipopolysaccharide (LPS)-induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS-induced inflammatory responses and glial activation. Pre-administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD+ precursor, increased NAD+ level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS-induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD+, NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF-κB signaling pathway in microglia. These results suggest that CD38-mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain. [ABSTRACT FROM AUTHOR]

Neuroinflammation is initiated by activation of the brain's innate immune system in response to an inflammatory challenge. Insufficient control of neuroinflammation leads to enhanced or prolonged pathology in various neurological conditions including multiple sclerosis and Alzheimer's disease. Nicotinamide adenine dinucleotide (NAD+) plays critical roles in cellular energy metabolism and calcium homeostasis. Our previous study demonstrated that deletion of CD38, which consumes NAD+, suppressed cuprizone‐induced demyelination, neuroinflammation, and glial activation. However, it is still unknown whether CD38 directly affects neuroinflammation through regulating brain NAD+ level. In this study, we investigated the effect of CD38 deletion and inhibition and supplementation of NAD+ on lipopolysaccharide (LPS)‐induced neuroinflammation in mice. Intracerebroventricular injection of LPS significantly increased CD38 expression especially in the hippocampus. Deletion of CD38 decreased LPS‐induced inflammatory responses and glial activation. Pre‐administration of apigenin, a flavonoid with CD38 inhibitory activity, or nicotinamide riboside (NR), an NAD+ precursor, increased NAD+ level, and significantly suppressed induction of cytokines and chemokines, glial activation and subsequent neurodegeneration after LPS administration. In cell culture, LPS‐induced inflammatory responses were suppressed by treatment of primary astrocytes or microglia with apigenin, NAD+, NR or 78c, the latter a specific CD38 inhibitor. Finally, all these compounds suppressed NF‐κB signaling pathway in microglia. These results suggest that CD38‐mediated neuroinflammation is linked to NAD+ consumption and that boosting NAD+ by CD38 inhibition and NR supplementation directly suppress neuroinflammation in the brain. [ABSTRACT FROM AUTHOR]