Brain interstitial fluid drainage and extracellular space affected by inhalational isoflurane: in comparison with intravenous sedative dexmedetomidine and pentobarbital sodium.

Brain interstitial fluid drainage and extracellular space are closely related to waste clearance from the brain. Different anesthetics may cause different changes of brain interstitial fluid drainage and extracellular space but these still remain unknown. Herein, effects of the inhalational isoflurane, intravenous sedative dexmedetomidine and pentobarbital sodium on deep brain matters' interstitial fluid drainage and extracellular space and underlying mechanisms were investigated. When compared to intravenous anesthetic dexmedetomidine or pentobarbital sodium, inhalational isoflurane induced a restricted diffusion of extracellular space, a decreased extracellular space volume fraction, and an increased norepinephrine level in the caudate nucleus or thalamus with the slowdown of brain interstitial fluid drainage. A local administration of norepinephrine receptor antagonists, propranolol, atipamezole and prazosin into extracellular space increased diffusion of extracellular space and interstitial fluid drainage whilst norepinephrine decreased diffusion of extracellular space and interstitial fluid drainage. These findings suggested that restricted diffusion in brain extracellular space can cause slowdown of interstitial fluid drainage, which may contribute to the neurotoxicity following the waste accumulation in extracellular space under inhaled anesthesia per se.

Bloodletting at Jing-well points decreases interstitial fluid flow in the thalamus of rats.

OBJECTIVE: To investigate the changes in the neuronal microenvironment of the middle cerebral artery (MCA) territory induced by Jing-well points bloodletting acupuncture (WPBA) and to explore the neuroprotective mechanism of WPBA in stroke. METHODS: Adult male Sprague Dawley (n = 32) rats were randomly divided into four groups of eight animals each: WPBA-thalamus group (WT), WPBA-caudate nucleus group (WC), sham-control thalamus group (ST) and sham-control caudate nucleus group (SC). Animals in the WT and WC groups received 2 µL of the extracellular tracer gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) injected into the thalamus or caudate nucleus, respectively, and 12 Jing-well points in the distal ends of the rats' digits were used for WPBA. Although 2 µL of Gd-DTPA was injected into the thalamus or caudate nucleus, respectively, for animals in the two sham groups (ST and SC), no acupuncture or bloodletting was performed. Brain extracellular space and interstitial fluid flow parameters were measured using Gd-DTPA-enhanced magnetic resonance imaging. RESULTS: The brain interstitial fluid flow speed was decreased in the thalamus after WPBA, with a significantly lower Gd-DTPA clearance rate and longer half-life of Gd-DTPA in the thalamus of treated rats than those in sham-control rats [WPBA-treated rats' clearance rate, (7.47 ± 3.15) x 10(-5)/s (P.= 0.009); half-life, (1.52 ± 0.13) h, P = 0.000]. By contrast, no significant changes in brain extracellular space and interstitial fluid flow parameters were detected in the caudate nucleus after WPBA (P = 0.649). In addition, no differences in the morphology of the brain extracellular space or the final distribution of the traced brain interstitial fluid were demonstrated between the WT and WC groups (P = 0.631, P = 0.970, respectively). CONCLUSION: The WPBA decreased the speed of the local thalamic ISF flow in rats, which is assumed to be a beneficial protection by down-modulated the metabolic rate of the attacked neurons under stroke.

Inactivation of ATP citrate lyase by Cucurbitacin B: A bioactive compound from cucumber, inhibits prostate cancer growth.

Prostate cancer, a leading cause of cancer-related deaths in males, is well recognized as having late disease on-set (mostly at age 60-70) and showing slow/latent disease development, and strategies to prevent cancer formation in late manhood may have significant health impacts. Cucurbitacin B (CuB) is a naturally occurring compound that is found abundantly in cucumbers and other vegetables, and it is known to exert anti-cancer activities (primarily via apoptosis-induction) in several human cancers. However, its chemopreventive potential for prostate cancer has not yet been investigated. Here, we reported that CuB significantly and specifically inhibited prostate cancer cell growth with low IC50 (~0.3 µM; PC-3 and LNCaP), accompanied by marked apoptosis (Caspase 3/7 activation, PARP cleavage, increase of Annexin V-Alexa Fluor 488 (Alexa488)+ cells and accumulation of Sub-G0/G1 population), whereas normal human prostate epithelial cells (PrEC) were CuB-insensitive. Using a chemopreventive model, pre-treatment of mice with CuB (2 weeks before PC-3 prostate cancer cell implantation) significantly reduced the rate of in vivo tumor-formation. A 79% reduction in tumor size (accompanied by marked in situ apoptosis) was observed in the CuB-treated group (with no noticeable toxicity) vs. controls at day 31. Strikingly, mechanistic investigations demonstrated that CuB drove dose-dependent inhibition of ATP citrate lyase phosphorylation (ACLY; an important enzyme for cancer metabolism) both in vitro and in the CuB-chemopreventive mouse model. Importantly, ACLY over-expression abrogated CuB's apoptotic effects in prostate cancer cells, confirming ACLY as a direct target of CuB. Thus, CuB harbors potent chemopreventive activity for prostate cancer, and we revealed a novel anti-tumor mechanism of CuB via inhibition of ACYL signaling in human cancer.

[Study on the morphological damage and cell apoptosis of nerve tissue in mice exposed to benzo[a]pyrene].

OBJECTIVE: To study the toxicological effects of benzo[a]pyrene(BaP) on mammalian animal's nerve tissue. METHODS: 50 Kunming mice were divided into 5 groups at random, the exposed groups(3 dose level groups), the vehicle control group and standard control group. Every group got 10 mice. The exposed groups were treated by intraperitoneal injection with BaP dissolved in vegetable oil at 7.8, 3.2 and 1.3 mg/kg respectively, 4 times/week, for 10 weeks, the vehicle control group were given vegetable oil and the standard control group were not given any treatment. All the mice were anesthetized with 0.02 mol/L pentobarbital and infused with 1.33 mol/L paraformaldehyde dissolved in PBS through heart after 10 weeks. Then the brain, spinal cord and sciatic nerve were removed. Slices of these tissues were made and morphological changes were observed by optical microscope and electron-microscope. Cell appoptosis was examined by TUNEL(TdT-mediated x-dUTP nick end labeling) method. RESULTS: Morphological observations showed tissue injury in BaP exposed groups. There were focal necrosis areas found in the high-dose group. The cell apoptosis rates in 3.2 and 1.3 mg/kg groups were 90.02%-94.22% and 62.45%-77.54% respectively, significantly higher than those of vehicle control group and standard control group(4.60%-5.57%). CONCLUSION: BaP is neurotoxic. It could damage the nerve tissue as well as induce DNA breaks and cell apoptosis.