Human amnionic progenitor cell secretome mitigates the consequence of traumatic optic neuropathy in a mouse model.

Traumatic optic neuropathy (TON) is a condition in which acute injury to the optic nerve from direct or indirect trauma results in vision loss. The most common cause of TON is indirect injury to the optic nerve caused by concussive forces that are transmitted to the optic nerve. TON occurs in up to 5% of closed-head trauma patients and there is currently no known effective treatment. One potential treatment option for TON is ST266, a cell-free biological solution containing the secretome of amnion-derived multipotent progenitor (AMP) cells. We investigated the efficacy of intranasal ST266 in a mouse model of TON induced by blunt head trauma. Injured mice treated with a 10-day regimen of ST266 showed an improvement in spatial memory and learning, a significant preservation of retinal ganglion cells, and a decrease in neuropathological markers in the optic nerve, optic tract, and dorsal lateral geniculate nucleus. ST266 treatment effectively downregulated the NLRP3 inflammasome-mediated neuroinflammation pathway after blunt trauma. Overall, treatment with ST266 was shown to improve functional and pathological outcomes in a mouse model of TON, warranting future exploration of ST266 as a cell-free therapeutic candidate for testing in all optic neuropathies.

Exogenous lipase administration alters gut microbiota composition and ameliorates Alzheimer's disease-like pathology in APP/PS1 mice.

Alzheimer's disease (AD) represents the most common form of dementia in the elderly with no available disease modifying treatments. Altered gut microbial composition has been widely acknowledged as a common feature of AD, which potentially contributes to progression or onset of AD. To assess the hypothesis that Candida rugosa lipase (CRL), which has been shown to enhance gut microbiome and metabolite composition, can rebalance the gut microbiome composition and reduce AD pathology, the treatment effects in APPswe/PS1de9 (APP/PS1) mice were investigated. The analysis revealed an increased abundance of Acetatifactor and Clostridiales vadin BB60 genera in the gut; increased lipid hydrolysis in the gut lumen, normalization of peripheral unsaturated fatty acids, and reduction of neuroinflammation and memory deficits post treatment. Finally, we demonstrated that the evoked benefits on memory could be transferred via fecal matter transplant (FMT) into antibiotic-induced microbiome-depleted (AIMD) wildtype mice, ameliorating their memory deficits. The findings herein contributed to improve our understanding of the role of the gut microbiome in AD's complex networks and suggested that targeted modification of the gut could contribute to amelioration of AD neuropathology.

Impact of gulf war toxic exposures after mild traumatic brain injury.

Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure. We observed that r-mTBI and GWI cumulatively affect the spatial memory of mice in the Barnes maze and result in a shift of search strategies employed by r-mTBI/GW exposed mice. GW exposure also produced anxiety-like behavior in sham animals, but r-mTBI produced disinhibition in both the vehicle and GW treated mice. Pathologically, GW exposure worsened r-mTBI dependent axonal degeneration and neuroinflammation, increased oligodendrocyte cell counts, and increased r-mTBI dependent phosphorylated tau, which was found to colocalize with oligodendrocytes in the corpus callosum. These results suggest that GW exposures may worsen TBI-related deficits. Veterans with a history of both GW chemical exposures as well as TBI may be at higher risk for worse symptoms and outcomes. Subsequent exposure to various toxic substances can influence the chronic nature of mTBI and should be considered as an etiological factor influencing mTBI recovery.

Repeated unpredictable stress and social isolation induce chronic HPA axis dysfunction and persistent abnormal fear memory.

The lack of progress in the psychopharmacological treatment of stress-related disorders such as PTSD is an ongoing crisis due to its negative socioeconomic implications. Current PTSD pharmacotherapy relies on a few FDA approved medications used primarily for depression which offer only symptomatic relief and show limited efficacy. As the population of PTSD patients is growing, the identification of effective etiology-based treatments for the condition is a high priority. This requires an in-depth understanding of the neurobiological and behavioral outcomes of stress in translationally relevant animal models. In this study, we use neuroendocrine, biochemical and behavioral measures to assess the HPA axis function and fear-memory deficits in a mouse model of chronic stress. The chronic stress procedures involved exposure to 21 days of repeated unpredictable stress (RUS), including predator stress, restraint and foot shock, followed by chronic social isolation. We show that mice exposed to our stress paradigm demonstrate exaggerated fear memory recall and blunted HPA axis functionality at one month after RUS. Our neuroendocrinal testing suggests that the attenuated stress response in our model may be related to an alteration in the adrenal MC2 receptor reactivity. While there was no noticeable change in pituitary negative feedback regulation mechanisms, CRH and phosphorylated Glucocorticoid receptors levels were altered in the hypothalamus. We also show that chronic supplementation with a peripheral glucocorticoid receptor agonist (low-dose dexamethasone) after RUS partially restores a number of stress-related behavioral deficits in the RUS model. This suggests a direct relationship between HPA axis function and behavior in our model. Our findings emphasize the importance of the adrenal receptors as a target for HPA axis dysfunction in stress and fear-related disorders.

Independent and combined effects of Bisphenol A and Diethylhexyl Phthalate on gestational outcomes and offspring development in Sprague-Dawley rats.

Bisphenol A (BPA) and Diethylhexyl Phthalate (DEHP) are well-studied endocrine disrupting chemicals (EDCs), however, the effects of mixtures of these EDCs are not. To assess the consequences of prenatal exposure to a mixture of these EDCs, dams were orally administered either saline (control), BPA (5 µg/kg BW/day), high dose DEHP (HD-D; 7.5 mg/kg BW/day), or a combination of BPA with HD-D in experiment 1; saline, BPA (5 µg/kg BW/day), low-dose DEHP (LD-D; 5 µg/kg BW/day) or a combination of BPA with LD-D in experiment 2. Gestational weights, number of abortions, litter size and weights, number of live births and stillbirths were recorded. Morphometric measures were obtained at birth and body weight, food and water intake were monitored weekly from postnatal weeks 3-12. Offspring were sacrificed at 16-24 weeks of age and organ weights were measured. The abortion rate of dams exposed to HD-D and the mixtures, BPA + LD-D and BPA + HD-D were higher at 9, 14 and 27% respectively. Prenatal exposure to BPA or HD-D significantly decreased relative thymus weights in male but not female offspring. Apoptotic cells were detected in thymus sections of both male and female offspring prenatally exposed to DEHP. Relative heart weights increased in BPA + HD-D exposed male offspring compared to the other groups. The results indicate that a mixture of BPA and DEHP, produced a pronounced effect on pregnancy outcomes. Male offspring appear to be more susceptible to the programming effects of these EDCs or their mixture suggesting a need to reconsider the possible additive, antagonistic or synergistic effects of EDC mixtures.

Chronic estrogen exposure affects gene expression in the rostral ventrolateral medulla of young and aging rats: Possible role in hypertension.

BACKGROUND: Chronic exposure to estradiol-17ß (E2) in adult female rats increases mean arterial pressure by stimulating superoxide production in the rostral ventrolateral medulla (RVLM). However the mechanisms behind this phenomenon are unknown. We hypothesized that E2 exposure induces the gene expression of cytokines, chemokines and NADPH oxidase (Nox) in the RVLM that promotes superoxide production and aging would exacerbate this effect. METHODS: Young adult (3-4 month old) and middle-aged (6-8 month old) female Sprague Dawley rats were sham-implanted (YS and MS respectively) or implanted s.c. with slow-release E2 pellets (20 ng of E2/day for 90 days; YE and ME respectively). Blood pressure (BP) was measured during the last 3 weeks of exposure in a separate set of rats. At the end of treatment, the animals were sacrificed and RVLM was isolated from the brainstem. PCR array and Quantitative RT-PCR were performed with the tissue to quantify genes associated with hypertension and superoxide production. Superoxide dismutase (SOD) activity was also measured in the RVLM from a different set of animals. RESULTS: E2 exposure increased mean arterial pressure in both YE and ME animals. Inflammatory genes such as interleukin-1ß, interleukin-6 and monocyte chemoattractant protein-1 were significantly up-regulated in the RVLM of ME treated female rats compared to YS rats, but not in YE rats. Endothelin-1 (ET-1) gene was up-regulated in the RVLM of both YE and ME rats that were exposed to E2. Furthermore, chronic E2 treatment increased the mRNA levels of Nox1 and Nox2 genes in the RVLM of YE but not ME animals. SOD activity was reduced in MA animals, compared to young animals. E2 treatment had no significant effect on SOD activity. CONCLUSION: Chronic E2 exposure stimulates the expression of inflammatory genes in older animals and increases the expression of Nox subunits in the RVLM of younger animals. SOD activity was reduced in older animals. This suggests increased superoxide production in younger animals, but reduced superoxide elimination in older animals. On the other hand, E2 exposure stimulates ET-1 expression in both young and aging animals. These findings suggest that hypertension caused by chronic E2 exposure may involve different molecular mediators in young and aging animals, however ET-1 and superoxide could be common mediators for both age groups.