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Two polyhydroxyfullerenes, which decrease organophosphate (OP)-induced acetylcholinesterase (AChE) inhibition in vitro, were administered by the intraperitoneal (ip) route or applied topically at doses of 0.9–24 mg/kg to protect adult male mice from enzyme-inhibiting and behavioral effects indicative of OP toxicity resulting from exposure to 1.7 - 2 mg/kg diphosphorofluoridate (DFP) ip or 2.3 – 2.7 mg paraoxon topical. Dosing paradigms included OP-fullerene simultaneous administration by the ip route, and 20 min post-OP polyhydroxyfullerene treatment topically. Benefits of OP sequestration by the polyhydroxyfullerene were noted and were dependent on the OP compound as well as timing and route of the polyhydroxyfullerene treatment. [ABSTRACT FROM AUTHOR]

Lanthionine synthetase cyclase-like receptor 2 (LANCL2) is a novel therapeutic target for Crohn’s disease (CD). BT-11 is a small molecule that binds LANCL2, is orally active, and has demonstrated therapeutic efficacy in 3 validated mouse models of colitis at doses as low as 8 mg/kg/d. Exploratory experiments evaluated BT-11 in male Harlan Sprague Dawley rats with a single oral dose of 500 mg/kg and 80 mg/kg/d for 14 days (n = 10 rats dosed/group). Treated and control rats were observed for behavioral detriments, and blood and tissues were collected for clinical pathology and histopathological examination. A functional observational battery demonstrated no differences between treated and control groups over multiple times of observation for quantal, categorical, and continuous end points, including posture, in cage activity, approach, response to touch, weight, grip strength, body temperature, and time on a rotarod. Histopathological examination of the brain, kidney, liver, adrenal gland, testes, stomach, small and large intestines, duodenum, pancreas, heart, lungs, spleen, thymus, and rib found no significant differences between the groups. Plasma enzymes associated with liver function were transiently elevated 2 to 4 days after the 500 mg/kg single dose but returned to normal values by 8 days and were not observed at any time in rats given 80 mg/kg/d for 14 days. One hour after oral administration of a single dose of 80 mg/kg, BT-11 had a maximal concentration of 21 ng/mL; the half-life was 3 hours. These experimental results demonstrated that BT-11 is well tolerated in rats, and, with further testing, may hold promise as an orally active therapeutic for CD. [ABSTRACT FROM AUTHOR]

Abstract: A study was conducted to determine if multiple exposures to several stress paradigms might affect the anticholinesterase effect of subsequently administered organophosphate insecticide chlorpyrifos. Male Sprague–Dawley rats were subject to daily periods of restraint, swimming, a combination of the two, or neither of the two (controls) (n =8/group) for 5 days per week over a six-week period. The most profound stress, as measured by reduced body weight gain and elevated levels of plasma corticosterone, was swimming. On day 39 of the study, shortly after the daily stress episode, one half of the rats in each group was dosed with 60 mg/kg chlorpyrifos subcutaneously. This had no effect on subsequent levels of plasma corticosterone. There were no stress-related differences in the degree of chlorpyrifos-induced inhibition of brain acetylcholinesterase in animals sacrificed on day 43. [Copyright &y& Elsevier]

Adult male Long-Evans rats were exposed to 2 neurotoxic organophosphates in a setting of chronic stress, over a 63-day period. The organophosphates were tri- ortho -tolyl phosphate (TOTP) administered in 14 gavage doses of 75, 150 or 300 mg/kg, and chlorpyrifos, given in two 60 mg/kg subcutaneous exposures. Corticosterone was added to the drinking water at 400 μg/ml, to model aspects of chronic stress. These compounds/dosages were administered individually and in combination, with appropriate controls, giving rise to 16 experimental groups. The major neuropathologic change was the presence of axonal degeneration progressing to myelinated fiber degeneration, mainly in distal regions of selected fiber tracts and peripheral nerve, seen in animals sacrificed on experimental day 63. The cervical spinal cord and medullary levels of the sensory gracile fasciculus were most prominently affected. This axonopathy/fiber degeneration was TOTP dose-related at the 300 and 150 mg/kg levels. There was association of this lesion with inhibition of the enzyme neurotoxic esterase in hippocampal tissue from TOTP-treated rats. Such an association categorizes this disease process as organophosphate ester-induced delayed neuropathy. Neither chlorpyrifos nor corticosterone appeared to contribute to the neuropathic events or the enzyme inhibition. A cohort of rats was maintained on the corticosterone dosing, but without additional exposure to TOTP or chlorpyrifos, for an additional 27 days. When these rats were examined on day 90, the nerve fiber degeneration had progressed in all experimental groups administered the 300 mg/kg dose of TOTP (lower doses were not studied at the 90-day interval), although hippocampal neurotoxic esterase had returned to control values. [ABSTRACT FROM AUTHOR]

The treatment of CNS disorders suffers from the inability to deliver large therapeutic agents to the brain parenchyma due to protection from the blood-brain barrier (BBB). Herein, we investigated high-frequency pulsed electric field (HF-PEF) therapy of various pulse widths and interphase delays for BBB disruption while selectively minimizing cell ablation. Eighteen male Fisher rats underwent craniectomy procedures and two blunt-tipped electrodes were advanced into the brain for pulsing. BBB disruption was verified with contrast T1W MRI and pathologically with Evans blue dye. High-frequency irreversible electroporation cell death of healthy rodent astrocytes was investigated in vitro using a collagen hydrogel tissue mimic. Numerical analysis was conducted to determine the electric fields in which BBB disruption and cell ablation occur. Differences between the BBB disruption and ablation thresholds for each waveform are as follows: 2-2-2 μ s (1028 V/cm), 5-2-5 μ s (721 V/cm), 10-1-10 μ s (547 V/cm), 2-5-2 μ s (1043 V/cm), and 5-5-5 μ s (751 V/cm). These data suggest that HF-PEFs can be fine-tuned to modulate the extent of cell death while maximizing peri-ablative BBB disruption. Furthermore, numerical modeling elucidated the diffuse field gradients of a single-needle grounding pad configuration to favor large-volume BBB disruption, while the monopolar probe configuration is more amenable to ablation and reversible electroporation effects. [ABSTRACT FROM AUTHOR]

Treatment of intracranial disorders suffers from the inability to accumulate therapeutic drug concentrations due to protection from the blood–brain barrier (BBB). Electroporation-based therapies have demonstrated the capability of permeating the BBB, but knowledge of the longevity of BBB disruption (BBBD) is limited. In this study, we quantify the temporal, high-frequency electroporation (HFE)-mediated BBBD in an in vivo healthy rat brain model. 40 male Fisher rats underwent HFE treatment; two blunt tipped monopolar electrodes were advanced into the brain and 200 bursts of HFE were delivered at a voltage-to-distance ratio of 600 V/cm. BBBD was verified with contrast enhanced T1W MRI (gadopentetate dimeglumine) and pathologically (Evans blue dye) at time points of 1, 24, 48, 72, and 96 h after HFE. Contrast enhanced T1W scans demonstrated BBBD for 1 to 72 h after HFE but intact BBB at 96 h. Histologically, tissue damage was restricted to electrode insertion tracks. BBBD was induced with minimal muscle contractions and minimal cell death attributed to HFE. Numerical modeling indicated that brief BBBD was induced with low magnitude electric fields, and BBBD duration increased with field strength. These data suggest the spatiotemporal characteristics of HFE-mediated BBBD may be modulated with the locally applied electric field. [ABSTRACT FROM AUTHOR]