Browsing by Author "Ortolani D."

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    Acute Chemogenetic Inhibition of Caudal NTS Astrocytes Reduced Systemic Blood Pressure in Rats Exposed to Chronic Intermittent Hypoxia-mimicking Sleep Apnea Syndrome
    (NLM (Medline), 2022) Iturriaga R.; Toledo C.; Ortolani D.; Del Rio R.
    © FASEB.Chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea, enhances carotid body (CB) discharges, leading to heightened sympathetic outflow and systemic hypertension. Previously, we found that CBs play a pivotal role in the hyperactivation of central nervous system (CNS) autonomic nuclei following CIH, particularly at the level of the caudal portion of the nucleus of the tractus solitary (NTS). Indeed, increased CB afferent activity during CIH increases the expression of pro-inflammatory cytokines in the NTS, suggesting that CBs may drive neuroinflammation at key cardiorespiratory regulatory areas. Astrocytes has been implicated in inflammatory processes at the CNS. However, the contribution of NTS astrocytes on the cardiorespiratory abnormalities following CIH has not been studied. Accordingly, we assessed the role of astrocytes residing within the NTS on the maintenance of hypertension following CIH. Male Sprague-Dawley rats (200 g) were exposed to CIH (5-6% inspired O2 for 20s, followed by room air for 280s, 12 times/h, 8 h/day, for 28 days). Arterial blood pressure (BP) was measured by indwelling telemetry. At 7 days of CIH exposure, rats were anesthetized and an adeno-associated virus (AAV; 450 nL, 1*10-12 vg) containing an inhibitory (Gi) Designer Receptor Exclusively Activated by Designer Drugs (DREADD) expressed under the control of the GFAP promoter was bilaterally injected into the caudal portion of the NTS using stereotaxic coordinates (-14.3 mm to bregma). At day 28 of CIH, hemodynamic and respiratory parameters were recorded before and after inhibition of NTS astrocytes with clozapine N-oxide (CNO, 1mg/kg, ip.). At the end of the experiments rats were transcardially perfused with 4% buffered paraformaldehyde, brains extracted and sectioned to assess astrocyte activation within the NTS. Twenty-eight days of CIH resulted in a significant 2-fold increase in NTS astrocyte activation as evidenced by enhanced reactivity of GFAP. Additionally, resting BP was markedly elevated compared to Sham conditions (MABP, 98±2 vs. 84±2 mmHg, CIH vs. Sham; p<0.05). Acute chemogenetic inhibition of NTS astrocytes following 28 days of CIH results in a significant reduction in BP (⁓10 mmHg; p<0.05). In addition, the exacerbated hemodynamic response triggered by acute hypoxic stimulation (Fi O2 10%) in rats exposed to CIH for 28 days was also reduced by NTS astrocyte inhibition ΔMABP, 30±2 vs. 15±2 mmHg, pre vs. post CNO; p<0.05). No cardiovascular effects of CNO alone were found in control rats that did not underwent AAV-DREADD-Gi injection into the NTS. Taken together, our results support a role for NTS astrocyte activation on the maintenance of hypertension following chronic CIH and suggest that activation of NTS astrocytes may participate in the CB-mediated cardiovascular reflex response during hypoxic stimulation.
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    Lipid-Encapsuled Grape Tannins Prevent Oxidative-Stress-Induced Neuronal Cell Death, Intracellular ROS Accumulation and Inflammation
    (MDPI, 2022) Diaz H.S.; Rios-Gallardo A.; Ortolani D.; Diaz-Jara E.; Flores M.J.; Vera I.; Rio R.D.; Monasterio A.; Osorio F.; Ortiz F.C.; Brossard N.
    © 2022 by the authors.The central nervous system (CNS) is particularly vulnerable to oxidative stress and inflammation, which affect neuronal function and survival. Nowadays, there is great interest in the development of antioxidant and anti-inflammatory compounds extracted from natural products, as potential strategies to reduce the oxidative/inflammatory environment within the CNS and then preserve neuronal integrity and brain function. However, an important limitation of natural antioxidant formulations (mainly polyphenols) is their reduced in vivo bioavailability. The biological compatible delivery system containing polyphenols may serve as a novel compound for these antioxidant formulations. Accordingly, in the present study, we used liposomes as carriers for grape tannins, and we tested their ability to prevent neuronal oxidative stress and inflammation. Cultured catecholaminergic neurons (CAD) were used to establish the potential of lipid-encapsulated grape tannins (TLS) to prevent neuronal oxidative stress and inflammation following an oxidative insult. TLS rescued cell survival after H2O2 treatment (59.4 ± 8.8% vs. 90.4 ± 5.6% H2O2 vs. TLS+ H2O2; p < 0.05) and reduced intracellular ROS levels by ~38% (p < 0.05), despite displaying negligible antioxidant activity in solution. Additionally, TLS treatment dramatically reduced proinflammatory cytokines’ mRNA expression after H2O2 treatment (TNF-α: 400.3 ± 1.7 vs. 7.9 ± 1.9-fold; IL-1β: 423.4 ± 1.3 vs. 12.7 ± 2.6-fold; p < 0.05; H2O2 vs. TLS+ H2O2, respectively), without affecting pro/antioxidant biomarker expression, suggesting that liposomes efficiently delivered tannins inside neurons and promoted cell survival. In conclusion, we propose that lipid-encapsulated grape tannins could be an efficient tool to promote antioxidant/inflammatory cell defense.