Increase, Pro-Inflammatory Mediators leads to Increase, Neural Remodeling

Modulating Factor 

Details 

Effects on the KER 

References 

Drug Therapy 

MW01-2-151SRM (MW-151) – water soluble, nontoxic, bioavailable compound that mitigates pro-inflammatory cytokine production, glial activation and inflammation in rat hippocampus. 

MW-151 reduced the neuroinflammation caused by 10 Gy of heavy ion exposure, thus preserving the integrity of neurogenic signaling in the dentate gyrus. 

Jenrow et al., 2013 

 Genetic Manipulation 

IL-1 receptor antagonist to prevent the interaction between IL-1β with IL-1R1.  

After 7 days in vitro, IL-1β significantly decreased the percentage of DCX-positive neurons, but pre-treatment and subsequent co-treatment with IL-1RA abolished this anti-neurogenic effect of IL-1β. 

Green et al., 2012 

 Hormone 

Histamine – an endogenous amine that can regulate both brain inflammation and neurogenesis. 

Histamine treatment significantly increased the total number cells, positively modulates hippocampal neurogenesis, ameliorates the loss of neuronal complexity of hippocampal neuroblasts and reverts synaptic plasticity loss caused by LPS. 

Saraiva et al., 2019 

Drug 

Tamoxifen – synthetic, non-steroidal estrogen receptor modulator with anti-inflammatory and neuroprotective properties. 

Tamoxifen decreased the production of inflammatory cytokines released from irradiated microglia, attenuating glial activation and decreasing neuronal apoptosis.  

Liu et al., 2010 

Drug 

Kukoamine A (KuA) – alkaloid extracted from traditional Chinese herb cortex lycii radicis that has been previously reported to have antioxidant properties.  

KuA inhibited radiation-induced increases in pro-inflammatory cytokines, alleviated the activation of hippocampal microglia and ameliorated the suppression of hippocampal neurogenesis. 

Zhang et al., 2017 

Genetics 

Polymorphism that increases the expression of APOE4  increases the risk of developing Alzheimer’s diseases, which generally consists of a decline in memory, thinking and language. 

In homozygous human APOE4 knock-in mice, a dramatic increase in pro-inflammatory cytokines TNF-α, IL-1β and IL-6 was seen after LPS injection compared to the APOE2 and APOE3 alleles, suggesting that APOE4 is implicated in a greater inflammatory response.  

Hunsberger et al., 2019; Zhu et al., 2012 

Reference 

Experiment Description 

Results 

Zonis et al., 2015 

In vitro. Adult female C57Bl/6 mice were treated with 3% wt/vol dextran sodium sulfate (DSS) using a multiple-cycle administration for up to 26 days. ELISA and qRT-PCR were used to measure cytokine levels in neural precursor cells and neural progenitor cell cultures. Western blot and immunostaining were used to measure Ki67 (neuronal cell proliferation marker), DCX (marker for neurogenesis), BLBP (marker for stem/early progenitor cells) and nestin (neural stem cell marker and involved in radial growth of axons). p21 (regulator of cell cycle progression at G1 and S phase) was also measured using these methods. 

Neural precursor cells (NPCs) treated with 50 ng/mL of IL-6 led to a decline in the % of   neuroblasts, with declines from 41% ± 6.4% in untreated cells to 22.39% ± 5.2% in IL-6-treated cells). Thus, decreasing neurogenesis was observed in in NPCs after DSS treatment. Chronic intestinal inflammation (29 days post-treatment) reduced hippocampal neurogenesis.  Evidence has highlighted that IL-1β and TNF-α mRNA levels were increased more than 2-fold, as well as a fourfold increase in p21 mRNA levels, which were accompanied by an approximate 2-fold down-regulation of progenitor cell proliferation and neurogenesis. Protein levels of IL-1β and TNF-α were not assessed.  

Jenrow et al., 2013 

In vivo. Adult male Fischer 344 rats were exposed to 10 Gy of whole-brain irradiation (WBI) using a 137Cs irradiator at a dose rate of 3.2 Gy/min. Rats also underwent mitigating therapy with MW01-2-151SRM (MW-151), a selective inhibitor of β amyloid-induced glial pro-inflammatory cytokine production that was initiated 24 h post-WBI and was continued for 28 days post-WBI by daily injection. Immunofluorescence assays for cell proliferation and neurogenesis were performed at 2 months and for neuroinflammation at 2 and 9 months post-WBI. 

MW-151 mitigated radiation-induced neuroinflammation, measured by OX-6+ cell densities, an indicator of pro-inflammatory level of activation, at 2- and 9-months post-irradiation. The 10 Gy group had mean OX-6+ cell densities of 1,966 (±218) and 1,493 (±270) cells/mm3, respectively. In the 10 Gy MW-151 group, the mean OX-6+ cell densities were significantly reduced  to 849 (±350) and 437 (±119) cells/mm3, respectively. In addition to this, 2 months post-irradiation, the mean DCX+ cell density, a marker for neurogenesis, was 1,375 (±535) cells/mm3 in the 10 Gy group, but was significantly increased  to 4,702 (±622) cells/mm3 after MW-151 therapy.  

Vallieres et al., 2002 

In vitro. Seizure was induced in transgenic mice expressing IL-6 under control of the glial fibrillary acidic protein (GFAP) promoter. Bromodeoxyuridine (BrdU) assay and immunofluorescence was used to detect proliferating neural progenitor cells and fluoro-jade staining was used to detect degenerating neurons. 

IL-6 compromised proliferation, survival, and differentiation of hippocampal progenitor cells when expressed over the long term (31 days) in young adult transgenic mice expressing the IL-6 transgene, causing a 63% decrease in the production rate of new neurons. The BrdU assay revealed a 27% reduction in progenitor cell proliferation, 53% reduction in progenitor cell survival in the dorsal hippocampus. 

Wong et al., 2004 

In vitro. Neural stem cell lines derived from adult C57BL/6 mice were allowed to proliferate and differentiate for 1 h to 3 days in the presence of IFN-γ and TNF-α. Proliferation and cytotoxicity assays were used to assess neural stem cell survival and their ability to differentiate and proliferate. 

IFN-γ (100 U/mL) and TNF-α (10 ng/mL) inhibited neural stem cell proliferation. The reduction was first significant at 4 days when control cells began to proliferate rapidly, and until day 6, control cells continued to proliferate while IFN-γ and TNF-α inhibited proliferation. 

Green et al., 2012 

In vitro. Rat hippocampal NPC cultures were treated with IL-1β (10 ng/mL) in the presence or absence of IL-1 receptor antagonist (IL-1RA), which prevents the interaction of IL-1β with IL-1R1. Cell proliferation analysis was performed, and RT-PCR and immunoblotting was used to measure DCX and cytokines. MTT assay was used to assess cell viability.  

Treatment with 10 ng/mL of IL-1β significantly decreased neurosphere circumference in a time-dependent manner. Compared to untreated cultures, a difference was seen at day 4, which continued until day 7. Neural integrity was assessed by examining the neural cell viability and proliferation IL-1β treatment for 24 hours after 4 days in vitro significantly decreased cell proliferation. IL-1β treatment for 7 days in vitro caused a significant decrease in cell viability compared to untreated cultures. 

Wu et al., 2012 

In vitro. Wild-type and IL-1βXAT C57BL/6 mice were exposed to Cre recombinase to induce IL-1β overexpression. Immunohistochemistry was used to measure IL-1β and DCX, a marker for migrating neuroblasts and neurogenesis.   

There was a significant effect of sustained IL-1β overexpression on adult neurogenesis one month after injection. A 94% decrease in migrating neuroblasts and neurogenesis was found, mirroring the pattern of neuroinflammation. 3 months post-injection, there was also an 87% reduction in neurogenesis. 

Chen and Palmer, 2013 

In vitro. Microglial cultures isolated from neonatal pups of C57BL/6 mice were treated with 1 μg/mL LPS, then incubated in neural stem cell (NSC) differentiation medium. The conditioned medium was then collected and applied to NSCs. Immunohistochemistry was used to measure cytokine levels and DCX, a marker for neurogenesis.  

After 72 h, neurogenesis significantly reduced in the differentiation culture after TNF-α injection of 20 ng/mL. One month after injection, proliferation and survival of endogenous neural stem cells decreased, as well as a reduction in neurogenesis. 

Saraiva et al., 2019 

In vitro. C57BL/6J male mice were injected with 1 or 2 mg/kg LPS. Histamine was also injected in the hippocampal dentate gyrus. The BrdU assay was used to quantify proliferating cells, while immunohistochemical analysis and western blot was used to measure IL-1β and DCX.  

In mice exposed to LPS, histamine significantly increased the total amount of proliferative cells. Mice exposed to 1 mg/kg of LPS had 98.8 ± 4.7 BrdU+ cells, a marker for proliferating cells, whereas 1 mg/kg of LPS + His had 197.6 ± 28.2 BrdU+ cells. 2 mg/kg of LPS yielded 96.7 ± 9.7 BrdU+ cells and 2 mg/kg of LPS + Histamine had 154.1 ± 23.8 BrdU+ cells. Histamine was also able to revert the LPS-induced loss of neuronal volume from 238.6 ± 19.7 (1 mg/kg LPS) to 331.1 ± 33.4 (1 mg/kg LPS + His) µm3. And 248.7 ± 18.8 (2 mg/kg LPS) to 334.3 ± 24.8 (2 mg/kg LPS + His) µm3. Postsynaptic density protein 95 (PSD-95) levels were also elevated due to histamine treatment (2 mg/kg LPS, 55.8 ± 9.9; 2 mg/kg LPS + His, 110.1 ± 12.9). 

Ryan et al., 2013 

In vitro. Adult Sprague Dawley rat dentate gyrus NPC cultures were prepared and treated with IL-1β (100 ng/mL) for 7 days. Immunohistochemistry was used to detect NPCs, proliferating cells and newly born cells. 

24 h after IL-1β treatment (100 ng/mL), there was no difference in proliferating neural cells relative to untreated cells. However, at 7 days post-treatment, there was a significant reduction in proliferating neural cells. There was also a decrease in neurogenesis. 

Dong et al., 2015 

In vitro. The mouse microglial cell line, BV-2, were irradiated with a single 16 Gy dose  of X-rays, then assessed at various time points up to 6 weeks. ELISA was used to measure levels of IL-1β and TNFα, whereas immunohistochemical staining was used to detect DCX+ cells. 

DCX+ cells, a marker of neurogenesis, were significantly reduced at 6 h until 2 weeks post-irradiation, which was accompanied by increased levels of IL-1β and TNF-α. TNF-α levels peaked at 3 h post-irradiation, decreased at 6 h, then increased in a time-dependent manner until 2 weeks. IL-1β levels increased in a time-dependent manner until peaking at 72 h, then spiked again at 6 weeks.