Apolar Extracts of St. John's Wort Alleviate the Effects of ß-Amyloid Toxicity in Early Alzheimer's Disease.

Hypericum perforatum (St. John's wort) has been described to be beneficial for the treatment of Alzheimer's disease (AD). Different extractions have demonstrated efficiency in mice and humans, esp. extracts with a low hypericin and hyperforin content to reduce side effects such as phototoxicity. In order to systematically elucidate the therapeutic effects of H. perforatum extracts with different polarities, APP-transgenic mice were treated with a total ethanol extract (TE), a polar extract obtained from TE, and an apolar supercritical CO2 (scCO2) extract. The scCO2 extract was formulated with silicon dioxide (SiO2) for better oral application. APP-transgenic mice were treated with several extracts (total, polar, apolar) at different concentrations. We established an early treatment paradigm from the age of 40 days until the age of 80 days, starting before the onset of cerebral ß-amyloid (Aß) deposition at 45 days of age. Their effects on intracerebral soluble and insoluble Aß were analyzed using biochemical analyses. Our study confirms that the scCO2H. perforatum formulation shows better biological activity against Aß-related pathological effects than the TE or polar extracts. Clinically, the treatment resulted in a dose-dependent improvement in food intake with augmentation of the body weight, and, biochemically, it resulted in a significant reduction in both soluble and insoluble Aß (-27% and -25%, respectively). We therefore recommend apolar H. perforatum extracts for the early oral treatment of patients with mild cognitive impairment or early AD.

Human immunodeficiency virus-1/simian immunodeficiency virus infection induces opening of pannexin-1 channels resulting in neuronal synaptic compromise: A novel therapeutic opportunity to prevent NeuroHIV.

In healthy conditions, pannexin-1 (Panx-1) channels are in a close state, but in several pathological conditions, including human immunodeficiency virus-1 (HIV) and NeuroHIV, the channel becomes open. However, the mechanism or contribution of Panx-1 channels to the HIV pathogenesis and NeuroHIV is unknown. To determine the contribution of Panx-1 channels to the pathogenesis of NeuroHIV, we used a well-established model of simian immunodeficiency virus (SIV) infection in macaques (Macaca mulatta) in the presence of and absence of a Panx-1 blocker to later examine the synaptic/axonal compromise induced for the virus. Using Golgi's staining, we demonstrated that SIV infection compromised synaptic and axonal structures, especially in the white matter. Blocking Panx-1 channels after SIV infection prevented the synaptic and axonal compromise induced by the virus, especially by maintaining the more complex synapses. Our data demonstrated that targeting Panx-1 channels can prevent and maybe revert brain synaptic compromise induced by SIV infection.

Gap junctions coordinate the propagation of glycogenolysis induced by norepinephrine in the pineal gland.

Chemical and electrical synapses are the two major communication systems that permit cell-to-cell communication within the nervous system. Although most studies are focused on chemical synapses (glutamate, γ-aminobutyric acid, and other neurotransmitters), clearly both types of synapses interact and cooperate to allow the coordination of several cell functions within the nervous system. The pineal gland has limited independent axonal innervation and not every cell has access to nerve terminals. Thus, additional communication systems, such as gap junctions, have been postulated to coordinate metabolism and signaling. Using acutely isolated glands and dissociated cells, we found that gap junctions spread glycogenolytic signals from cells containing adrenoreceptors to the entire gland lacking these receptors. Our data using glycogen and lactate quantification, electrical stimulation, and high-performance liquid chromatography with electrochemical detection, demonstrate that gap junctional communication between cells of the rat pineal gland allows cell-to-cell propagation of norepinephrine-induced signal that promotes glycogenolysis throughout the entire gland. Thus, the interplay of both synapses is essential for coordinating glycogen metabolism and lactate production in the pineal gland.

Mechanisms of HIV-mediated blood-brain barrier compromise and leukocyte transmigration under the current antiretroviral era.

HIV-associated neurological compromise is observed in more than half of all people with HIV (PWH), even under antiretroviral therapy (ART). The mechanism has been associated with the early transmigration of HIV-infected monocytes across the BBB in a CCL2 and HIV replication-dependent manner. However, the mechanisms of chronic brain damage are unknown. We demonstrate that all PWH under ART have elevated circulating ATP levels that correlate with the onset of cognitive impairment even in the absence of a circulating virus. Serum ATP levels found in PWH with the most severe neurocognitive impairment trigger the transcellular migration of HIV-infected leukocytes across the BBB in a JAM-A and LFA-1-dependent manner. We propose that targeting transcellular leukocyte transmigration could reduce or prevent the devastating consequences of HIV within the brains of PWH under ART.

Evaluation of cerebrospinal fluid (CSF) and interstitial fluid (ISF) mouse proteomes for the validation and description of Alzheimer's disease biomarkers.

BACKGROUND: Mass spectrometry (MS)-based cerebrospinal fluid (CSF) proteomics is an important method for discovering biomarkers of neurodegenerative diseases. CSF serves as a reservoir for interstitial fluid (ISF), and extensive communication between the two fluid compartments helps to remove waste products from the brain. NEW METHOD: We performed proteomic analyses of both CSF and ISF fluid compartments using intracerebral microdialysis to validate and detect novel biomarkers of Alzheimer's disease (AD) in APPtg and C57Bl/6J control mice. RESULTS: We identified up to 625 proteins in ISF and 4,483 proteins in CSF samples. By comparing the biofluid profiles of APPtg and C57Bl/6J mice, we detected 37 and 108 significantly up- and downregulated candidates, respectively. In ISF, 7 highly regulated proteins, such as Gfap, Aldh1l1, Gstm1, and Txn, have already been implicated in AD progression, whereas in CSF, 9 out of 14 highly regulated proteins, such as Apba2, Syt12, Pgs1 and Vsnl1, have also been validated to be involved in AD pathogenesis. In addition, we also detected new interesting regulated proteins related to the control of synapses and neurotransmission (Kcna2, Cacng3, and Clcn6) whose roles as AD biomarkers should be further investigated. COMPARISON WITH EXISTING METHODS: This newly established combined protocol provides better insight into the mutual communication between ISF and CSF as an analysis of tissue or CSF compartments alone. CONCLUSIONS: The use of multiple fluid compartments, ISF and CSF, for the detection of their biological communication enables better detection of new promising AD biomarkers.

ABC Transporter C1 Prevents Dimethyl Fumarate from Targeting Alzheimer's Disease.

Alzheimer's disease (AD), the leading cause of dementia, is a growing health issue with very limited treatment options. To meet the need for novel therapeutics, existing drugs with additional preferred pharmacological profiles could be recruited. This strategy is known as 'drug repurposing'. Here, we describe dimethyl fumarate (DMF), a drug approved to treat multiple sclerosis (MS), to be tested as a candidate for other brain diseases. We used an APP-transgenic model (APPtg) of senile ß-amyloidosis mice to further investigate the potential of DMF as a novel AD therapeutic. We treated male and female APPtg mice through drinking water at late stages of ß-amyloid (Aß) deposition. We found that DMF treatment did not result in modulating effects on Aß deposition at this stage. Interestingly, we found that glutathione-modified DMF interacts with the ATP-binding cassette transporter ABCC1, an important gatekeeper at the blood-brain and blood-plexus barriers and a key player for Aß export from the brain. Our findings suggest that ABCC1 prevents the effects of DMF, which makes DMF unsuitable as a novel therapeutic drug against AD. The discovered effects of ABCC1 also have implications for DMF treatment of multiple sclerosis.

Deepening inequalities: What did COVID-19 reveal about the gendered nature of academic work?

This study discusses the gendered nature of the transformation of academic work, which has been accelerated by the COVID-19 pandemic. We collected empirical material in spring 2020, at the peak of the pandemic, via 28 interviews with academics in Poland. The results illustrate the far-reaching and lasting impacts of the pandemic on academia that reinforce existing gender inequalities and bring new ones. The study also reveals the invisible academic work, which is performed mostly by female faculty. This work, neither recognized nor rewarded in the course of women's academic careers, deepens the gendered organization of work in higher education institutions.

The Glutamate System as a Crucial Regulator of CNS Toxicity and Survival of HIV Reservoirs.

Glutamate (Glu) is the most abundant excitatory neurotransmitter in the central nervous system (CNS). HIV-1 and viral proteins compromise glutamate synaptic transmission, resulting in poor cell-to-cell signaling and bystander toxicity. In this study, we identified that myeloid HIV-1-brain reservoirs survive in Glu and glutamine (Gln) as a major source of energy. Thus, we found a link between synaptic compromise, metabolomics of viral reservoirs, and viral persistence. In the current manuscript we will discuss all these interactions and the potential to achieve eradication and cure using this unique metabolic profile.

Circulating levels of ATP is a biomarker of HIV cognitive impairment.

BACKGROUND: In developed countries, Human Immunodeficiency Virus type-1 (HIV-1) infection has become a chronic disease despite the positive effects of anti-retroviral therapies (ART), but still at least half of the HIV infected population shown signs of cognitive impairment. Therefore, biomarkers of HIV cognitive decline are urgently needed. METHODS: We analyze the opening of one of the larger channels expressed by humans, pannexin-1 (Panx-1) channels, in the uninfected and HIV infected population (n = 175). We determined channel opening and secretion of intracellular second messengers released through the channel such as PGE2 and ATP. Also, we correlated the opening of Panx-1 channels with the circulating levels of PGE2 and ATP as well as cogntive status of the individuals analyzed. FINDINGS: Here, we demonstrate that Panx-1 channels on fresh PBMCs obtained from uninfected individuals are closed and no significant amounts of PGE2 and ATP are detected in the circulation. In contrast, in all HIV-infected individuals analyzed, even the ones under effective ART, a spontaneous opening of Panx-1 channels and increased circulating levels of PGE2 and ATP were detected. Circulating levels of ATP were correlated with cognitive decline in the HIV-infected population supporting that ATP is a biomarker of cognitive disease in the HIV-infected population. INTERPRETATION: We propose that circulating levels of ATP could predict CNS compromise and lead to the breakthroughs necessary to detect and prevent brain compromise in the HIV-infected population.

Effects of exposure to 5-MeO-DIPT during adolescence on brain neurotransmission and neurotoxicity in adult rats.

PURPOSE: Tryptamine hallucinogen 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is a serotonin transporter inhibitor with high affinity for serotonin 5-HT1A and 5-HT2A/C receptors. We showed previously that 5-MeO-DIPT in a single dose increased neurotransmitter release in brain regions of rats and elicited single- and double-strand DNA breaks. Herein we investigated the effects of repeated-intermittent 5-MeO-DIPT administration in adolescence on dopamine (DA), serotonin (5-HT) and glutamate release in brain regions of adult rats. Furthermore, we examined caspase-3 activity, oxidative DNA damage, the Gpx3, Sod1, Ht1a and Ht2a mRNA expression levels, and cell viability. METHODS: Neurotransmitter release was measured by microdialysis in freely moving animals. Caspase-3 activity was assessed colorimetrically, and oxidative DNA damage with the comet assay, while the Gpx3, Sod1, Ht1a and Ht2a mRNA expression levels were assessed by real-time polymerase chain reaction. Cell viability was studied in SH-SY5Y and Hep G2 cells by the MTT test. RESULTS: We observed changed responses of DA, 5-HT and glutamate neurons to a challenge dose of 5-MeO-DIPT when animals were treated repeatedly in adolescence with this hallucinogen. The basal extracellular levels of DA and 5-HT were decreased in the striatum and nucleus accumbens, while glutamate level was increased in the nucleus accumbens and frontal cortex. The damage of cortical DNA, increased Gpx3 and Sod1 mRNA expression and affected caspase-3 activity were also observed. Furthermore, decreased Ht1a and Ht2a mRNA expression in the frontal cortex and marked cytotoxicity of 5-MeO-DIPT were found. CONCLUSIONS: These results suggest that 5-MeO-DIPT given repeatedly during adolescence affects brain neurotransmission and shows neurotoxic potential observed in adult animals.

The effect of repeated-intermittent exposure to 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) during adolescence on learning and memory in adult rats.

BACKGROUND: According to the European Drug Report, the use of novel psychoactive substances (NPS) is constantly growing. NPS are widely abused by human adolescent subjects. 5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT) is one of the most frequently used hallucinogenic NPS. 5-MeO-DIPT intoxication results in hallucinations, vomiting, and tachycardia. Long-term exposure to 5-MeO-DIPT was reported to lead to development of post-hallucinogenic perception disorder. The aim of the present study was to determine whether repeated-intermittent administration of 5-MeO-DIPT during adolescence affects learning and memory in adult rats. METHODS: Rats were treated with 5-MeO-DIPT in a dose of 2.5mg/kg from 30 to 33 and 37 to 40 Postnatal Day (PND). The experiments were conducted when the animals reached 90 PND. The effect of 5-MeO-DIPT on cognitive functions was assessed using the novel object recognition, open field, and serial pattern learning (SPL) tests. RESULTS: Repeated-intermittent exposure to 5-MeO-DIPT during adolescence decreased the number of crossings in the open field test at adulthood. Moreover, 5-MeO-DIPT treatment impaired adult rats' learning in the SPL test. There was no change in the novel object recognition test. CONCLUSIONS: The present results show that the performance of adult rats treated with 5-MeO-DIPT during adolescence was impaired in the open field test, which indicates the attenuated exploratory activity. 5-MeO-DIPT treatment undermined adult rats' performance in the serial pattern learning test, suggesting impairment of long term memory and cognitive flexibility. The present study showed that the exposure to 5-MeO-DIPT during adolescence might lead to long-lasting behavioral changes which persisted long after the exposure period.

Neurochemical and Neurotoxic Effects of MDMA (Ecstasy) and Caffeine After Chronic Combined Administration in Mice.

MDMA (3,4-methylenedioxymethamphetamine) is a psychostimulant popular as a recreational drug because of its effect on mood and social interactions. MDMA acts at dopamine (DA) transporter (DAT) and serotonin (5-HT) transporter (SERT) and is known to induce damage of dopamine and serotonin neurons. MDMA is often ingested with caffeine. Caffeine as a non-selective adenosine A1/A2A receptor antagonist affects dopaminergic and serotonergic transmissions. The aim of the present study was to determine the changes in DA and 5-HT release in the mouse striatum induced by MDMA and caffeine after their chronic administration. To find out whether caffeine aggravates MDMA neurotoxicity, the content of DA and 5-HT, density of brain DAT and SERT, and oxidative damage of nuclear DNA were determined. Furthermore, the effect of caffeine on MDMA-induced changes in striatal dynorphin and enkephalin and on behavior was assessed. The DA and 5-HT release was determined with in vivo microdialysis, and the monoamine contents were measured by HPLC with electrochemical detection. DNA damage was assayed with the alkaline comet assay. DAT and SERT densities were determined by immunohistochemistry, while prodynorphin (PDYN) and proenkephalin were determined by quantitative PCR reactions. The behavioral changes were measured by the open-field (OF) test and novel object recognition (NOR) test. Caffeine potentiated MDMA-induced DA release while inhibiting 5-HT release in the mouse striatum. Caffeine also exacerbated the oxidative damage of nuclear DNA induced by MDMA but diminished DAT decrease in the striatum and worsened a decrease in SERT density produced by MDMA in the frontal cortex. Neither the striatal PDYN expression, increased by MDMA, nor exploratory and locomotor activities of mice, decreased by MDMA, were affected by caffeine. The exploration of novel object in the NOR test was diminished by MDMA and caffeine. Our data provide evidence that long-term caffeine administration has a powerful influence on functions of dopaminergic and serotonergic neurons in the mouse brain and on neurotoxic effects evoked by MDMA.

The effect of caffeine on MDMA-induced hydroxyl radical production in the mouse striatum.

BACKGROUND: The psychostimulant 3,4-methylenedioxymethamphetamine (MDMA) with a strong addictive potential is widely used as a recreational drug. Neurotoxicity of MDMA is related with the generation of highly reactive free radicals. METHODS: MDMA was given in doses of 20 and 40mg/kg ip alone or in combination with caffeine (CAF) 10mg/kg ip. Extracellular concentration of hydroxyl radical was measured using microdialysis in freely moving mice and was assayed by HPLC with electrochemical detection. RESULTS: MDMA dose-dependently increased production of hydroxyl radical in the mouse striatum and its effect was reversed by caffeine. CONCLUSIONS: The data show that caffeine may have neuroprotective properties as it decreased oxidative stress induced by MDMA.