Using the model of hypoxia-hypoglycemia (HH) in rat brain slices, we asked whether glutamate transmission is altered following a brief HH episode. The HH challenge was conducted by exposing slices to a glucose-free medium aerated with 95% N2-5% CO2, for approximately 4 min, and glutamate transmission in the hippocampal CA1 region was monitored at different post HH times. In slices examined

The present experiments were designed to elucidate the time frame in which an evoked cholinergic impulse decreases the Ca2+-dependent K+ current (IsAHP) in hippocampal CA1 neurons, and to determine to what extent acetylcholinesterase (AChE) inhibitors enhance the efficacy of the cholinergic impulse. Whole cell voltage-clamp recordings were performed on hippocampal CA1 neurons of rat brain slices and IsAHPs were evoked by constant depolarizing pulses. Cholinergic afferent fibers in stratum oriens were stimulated electrically and the time interval between the afferent stimulus and the depolarizing pulse was varied from 1 to 30 s. In slices perfused with the standard external medium, the afferent stimulus caused a profound decrease in the following IsAHP only when the stimulus preceded the depolarizing pulse by 1-2 s. The stimulus was without effects on the IsAHP when applied >/=5s before the depolarizing pulse. The effects of the afferent stimulus were greatly enhanced in CA1 neurons exposed to the catalytic AChE inhibitors neostigmine, physostigmine, or 9-amino-1,2,3, 4-tetrahydro-acridine. A substantial decrease in the IsAHP was observed even when the stimulus preceded the depolarizing pulse by >/=30 s. However applications of peripheral site AChE inhibitors decamethonium and propidium caused only minor or no enhancement of the IsAHP reduction after the afferent stimulus. We suggest in physiological conditions that muscarinic modulation of ionic conductances of CNS neurons has a limited time course after a cholinergic impulse and that the modulation is greatly enhanced and prolonged when catalytic activities of AChEs are suppressed pharmacologically.

Bis(3)-tacrine is a dimeric AChE inhibitor derived from tacrine with a potential to treat Alzheimer’s disease. It was recently been reported to act as a fast off-rate antagonist of NMDA receptors with moderate affinity. In the present study, we aimed to explore whether bis(3)-tacrine could modulate the function of native sustained potassium current in cultured rat hippocampal neurons using whole-cell patch-clamp technique. We found that bis(3)-tacrine inhibited the amplitude of sustained potassium current in a reversible and concentration-dependent manner, with a potency two orders of magnitude higher than that of tacrine. The inhibition was voltage-independent between 0 to +60 mV. The IC50 values for bis(3)-tacrine and tacrine inhibition of sustained potassium current were 0.450.07 and 50.54.8 μM, respectively. I-V curves showed a more potent inhibition of sustained potassium current by bis(3)-tacrine (1 μM) compared to tacrine at the same concentration. Bis(3)-tacrine hyperpolarized the activation curve of the current by 11.2 mV, albeit leaving the steady-state inactivation of the current unaffected.

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Purpose/Objective(s): Vestibular schwannomas (VS) are treated with fractionated stereotactic radiosurgery (SRS) to attempt hearing preservation. There are no established predictors of longitudinal effect on tumor volume, pseudoprogression or necrosis. Materials/Methods: An institutional review board approved retrospective review of patients treated with 1, 3, or 5 fraction (fx) SRS for VS at our institution from 1998-2016, with at least 2 years of follow-up was performed. Radiographic follow-up by MRI was used to calculate tumor volume based on tridimensional measurements and non-spherical tumor volume was approximated by pi/6*x*y*z. Radiologic responders were those with reduction by at least 2mm in any dimension. Radiologic nonresponders had no growth or reduction. Treatment failures grew at least 2mm in any dimension by last follow-up. Pseudoprogression was defined as any interval increase in tumor volume that later normalized or reduced to below baseline tumor volume. Results: A total of 56 patients met selection criteria. Most patients were treated with 5 fractions (32, 57%), then 3 fractions (12, 21%) and 1 fraction (12, 21%). The most common dose and fractionation regimens were 1250 cGy x 1 (7, 12.5%), 700 cGy x 3 (12, 21.4%), 500 cGy x 5 (12, 21.4%), and 450 cGy x 5 (14, 25%). Patients treated with 1 fx had a median baseline tumor volume of 1.2 cc (range 0.04-3.88), median dose 1250 cGy per fx (range 1200-1600), and median percent reduction in tumor volume of 2.7 % (range-396 to 85). Patients treated with 3 fxs had a median baseline tumor volume of 1.2 cc (range 0.4-7.7), median dose of 700 cGy (range 700-700), and a median percent reduction in tumor volume of 24 % (range-272 to 92). Patients treated with 5 fxs had a median baseline tumor volume of 2.0 cc (range 0.07-7.49), median dose of 450 cGy (range 400-550), and a median percent reduction in tumor volume of 6 % (range-290 to 89). Regardless of the number of fxs, patients had similar rates of pseudoprogression (25% in single, 33% in 3 fx and 31% in 5 fx cohorts). Patients treated with 3 fxs had lower rates of radiographic necrosis (58% with 3 fx vs 75% with 1 or 5 fx) but higher rates of radiologic response (67% with 3 fx vs 33% with 1 fx or 44% with 5 fx) and lower rates of radiologic non-response (17% with 3 fx vs 58% with 1 fx or 38% with 5 fx). Patients with more fxs had higher rates of treatment failure (8% with 1 fx vs 17% with 3 fx or 19% with 5 fx). Conclusion: SRS with 1, 3, or 5 fxs was safe and effective in reducing tumor volume of VS. About one-third of all patients had evidence of pseudoprogression. Patients treated with 3 fx SRS had the largest % reduction in tumor volume (median 24%) and lowest rates of necrosis.