Hsp90ß inhibitors prevent GLT-1 degradation but have no beneficial efficacy on absence epilepsy.

The loss of glutamate transporter-1 (GLT-1) is associated with temporal lobe epilepsy (TLE). A recent study reported that Hsp90ß interacted with GLT-1 and recruited it to 20S proteasome for degradation. Therefore, inhibiting Hsp90ß may be a new strategy for treating epilepsy. So far, no studies have shown whether the inhibition of Hsp90ß had therapeutic effects on absence epilepsy. Using a model of absence epilepsy, we demonstrated that 17-allylamino-17-demethoxygeldanamycin (17AAG) and Ganetespib (STA9090) had no therapeutic effect. Although this is a negative result, it also has a meaningful exploration value for whether Hsp90 inhibitors have therapeutic effects on other epilepsy types.

The effect of intravesical hyaluronic acid therapy on urodynamic and clinical outcomes among women with interstitial cystitis/bladder pain syndrome.

OBJECTIVE: Treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) is often delayed because of a lack of objective data during diagnosis. This study was conducted to determine the clinical validity of using urodynamic studies to investigate the effect of intravesical hyaluronic acid (HA) treatment among women with IC/BPS. MATERIALS AND METHODS: Thirty patients with IC/BPS undergoing 6-month intravesical instillation of HA were recruited. Pretreatment evaluation involved a urinalysis and urinary culture, urinary cytology, a 3-day voiding diary, and cystoscopy with hydrodistention of the bladder. Urodynamic study was performed before and after HA treatment. Symptomatic changes were assessed using a questionnaire covering lower urinary tract symptoms, the O'Leary-Sant symptom index and problem indexes (ICSI and ICPI), and the visual analog scale for pain and urgency. Patient demographics, urinary symptoms, ICSI/ICPI scores, pain and urgency scores, and urodynamic results before and after HA treatment were compared. RESULTS: Urinary frequency, nocturia, urgency, pelvic pain, bladder capacity, ICSI, and ICPI were significantly improved after HA treatment. Comparing urodynamic parameters, the volumes at first desire to void (FDV) and maximum cystometric capacity were significantly increased after HA treatment. Before HA treatment, a negative correlation existed between the ICSI and ICPI and urodynamic parameters, including maximum flow rate and bladder capacity, but there were no significant correlations after treatment. Before HA treatment, a negative correlation was discovered between nocturia and FDV. However, after HA treatment, there were no significant correlations between urinary symptoms and urodynamic parameters. CONCLUSIONS: Our results indicate that the improvement of urinary symptoms of IC/BPS after HA treatment is associated with increased FDV and maximum cystometric capacity. The value of FDV and the frequency of nocturia after treatment may become useful objective indicators for prognosis of IC/BPS.

Amphetamine inhibits the N-methyl-D-aspartate receptor-mediated responses by directly interacting with the receptor/channel complex.

Amphetamine (AMPH) induces behavioral sensitization and neurotoxicity primarily by enhancing the dopamine-mediated neurotransmission. However, the involvement of the N-methyl-D-aspartate (NMDA) receptor in AMPH-induced neuropathology is also known. Recent investigation has found that high concentration of dopamine could inhibit NMDA receptor-mediated responses by blocking the NMDA receptor channel. By virtue of the structure similarity between dopamine and AMPH, we determined whether d-AMPH and its analogs, l-AMPH and methamphetamine (MAMH), could affect the NMDA receptor-mediated [3H]N-[1-(2-thienyl)cyclohexyl] piperidine ([3H]TCP) binding in rat cortical membrane preparations and intracellular 45Ca2+ accumulation and cell death in the rat primary cortical cell cultures. AMPH concentration-dependently inhibited NMDA- and glycine-stimulated [3H]TCP binding and intracellular 45Ca2+ accumulation with two distinct potencies; a minor inhibition with high potency and a major inhibition with low potency. [3H]TCP binding suggested that the high-potency inhibition was produced by decreasing agonist-induced activation of the NMDA receptor channel. On the other hand, the low-potency inhibition was produced by competing with [3H]TCP binding in the NMDA receptor channel, like the action of noncompetitive antagonist of the NMDA receptor. However, AMPH analogs were less potent in inhibiting NMDA- and glycine-induced cultured cell death. Thus, this result indicates that AMPH could antagonize the NMDA receptor-mediated responses in vitro by two different mechanisms, probably, through directly interacting with two distinct sites on this receptor/channel complex.