Sertoli cell grafts for Huntington's disease. An opinion

The role of inflammation in CNS diseases is controversial, but growing evidence suggests that antiinflammatory agents can minimize and/or prevent neural degeneration and its associated behavioral consequences. Sertoli cells can be grafted into the CNS to locally deliver molecules with known trophic and anti-inflammatory effects on the surrounding tissue. When sertoli cells are grafted into the 3-nitropropionic acid (3-NP) model of Huntington's disease the protective effects are quite similar to those obtained using systemic treatments with NSAIDS (Salzberg-Benhouseet al., J. Pharmacol. Exp. Ther. 306:218–228, 2003). While these data alone do not provide unequivocal support for the notion that Sertoli cell grafts exert their beneficial effects via modulating local inflammation, they do provide an interesting convergence between data sets. The benefits of Sertoli cells grafts should be more thoroughly examined in animal models of inflammation.     

Effects of 6-hydroxydopamine-induced catecholamine depletion on shock-precipitated wall climbing of infant rat pups

Sprague-Dawley rat pups were intracisternally injected with 6-hydroxydopamine (6OHDA) or vehicle on postnatal Day 3 and tested for footshock-precipitated wall climbing behavior every 48 hr from postnatal Days 5 through 17. The 6OHDA treatment was observed to lower brain catecholamine levels, particularly in forebrain, and to decrease the incidence of wall climbing. This attenuation in the amount of wall climbing did not appear to be related to any neurotoxin-induced alterations in general motor activity, body weight, or body temperature. It also did not appear that the depression in wall climbing seen in 6OHDA-treated animals was related to an observed neurotoxin-induced increase in shock sensitivity, given that amount of wall climbing was observed to be positively correlated with footshock intensity. These results provide further support that catecholaminergic systems are involved in the elicitation of wall climbing behavior. The 6OHDA treatment did not alter the ontogenetic time course of disappearance of this behavior pattern, suggesting that maturational changes occurring in forebrain catecholaminergic terminals may not be critical for the dissipation of wall climbing following the second postnatal week.     

Vivitrex, an injectable, extended-release formulation of naltrexone, provides pharmacokinetic and pharmacodynamic evidence of efficacy for 1 month in rats.

While oral naltrexone is effective in treating alcohol and opiate dependencies, poor patient adherence and widely fluctuating plasma levels limit its efficacy. To overcome these problems, an extended-release formulation of naltrexone (Vivitrex) was developed by encapsulating naltrexone into injectable, biodegradable polymer microspheres. Pharmacokinetic studies in rats demonstrated that this formulation produced stable, pharmacologically relevant plasma levels of naltrexone for approximately 1 month following either subcutaneous or intramuscular injections. While rats receiving placebo microspheres demonstrated a pronounced analgesic response to morphine in the hot-plate test, morphine analgesia was completely blocked in rats treated with extended-release naltrexone. This antagonism began on day 1 following administration and lasted for 28 days. Rats reinjected with extended-release naltrexone 34 days after the initial dose and tested for another 35 days showed consistent suppression of morphine analgesia for an additional 28 days. mu-Opioid receptor density, as measured by [(3)H]DAMGO autoradiography, increased up to two-fold following a single injection of extended-release naltrexone. Saturation binding assays using [(3)H]DAMGO showed changes in the midbrain and striatum at 1 week after extended-release naltrexone administration, and after 1 month in the neocortex. These receptor increases persisted for 2-4 weeks after dissipation of the morphine antagonist actions of naltrexone. These data suggest that therapeutically relevant plasma levels of naltrexone can be maintained using monthly injections of an extended-release microsphere formulation, and that changes in mu-opioid receptor density do not impact its efficacy in suppressing morphine-induced analgesia in the rat. Clinical trials of extended release naltrexone for treating alcohol and opiate dependency are currently ongoing.     

P21WAF1, P27KIP1, TP53 and C-MYC analysis in 204 ovarian carcinomas treated with platinum-based regimens.

BACKGROUND: The prognostic and predictive value of cell cycle regulatory proteins in ovarian cancer has not been established. We evaluated the clinical and biological significance of P21(WAF1), P27(KIP1), C-MYC, TP53 and Ki67 expressions in ovarian cancer patients. MATERIALS AND METHODS: Immunohistochemical analysis was performed on 204 ovarian carcinomas of International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IV treated with platinum-based chemotherapy. Multivariate analysis with Cox and logistic regression models was performed in the whole group, and in the TP53-negative and TP53-positive subgroups. RESULTS: High P21(WAF1) labeling index (LI) was an independent positive predictor of platinum-sensitive response (P = 0.02). Overall survival was positively influenced by P21(WAF1) LI (P = 0.02) or by P21(WAF1) plus P27(KIP1) LI (P = 0.004) in the TP53-negative group only. Ki67 LI showed borderline association with disease-free survival (P = 0.05). Growth fraction was negatively associated with P21(WAF1) and P27(KIP1) indices in the TP53-negative group (P = 0.023 and 0.008, respectively), and these associations were borderline or lost in the TP53-positive group. Endometrioid and clear cell carcinomas differed from other carcinomas by having a low incidence of TP53 accumulation, a high incidence of C-MYC overexpression (70%) and a low median Ki67 LI (all with P <0.001). CONCLUSIONS: We have shown an independent predictive value of P21(WAF1) LI in ovarian carcinoma patients. The prognostic value of P21(WAF1) and P21(WAF1) plus P27(KIP1) LI was determined by TP53 status. A high frequency of C-MYC overexpression in endometrioid and clear cell carcinomas may suggest its role in the development of these tumor types.