Tiago Luis Dedavid e Silva

Molecular pharmacological dissection of short- and long-term memory.

Abstract1. It has been discussed for over 100 years whether short-term memory (STM) is separate from, or just an early phase of, long-term memory (LTM). The only way to solve this dilemma is to find out at least one treatment that blocks STM while keeping LTM intact for the same task in the same animal.2. The effect of a large number of treatments infused into the hippocampus, amygdala, and entorhinal, posterior parietal or prefrontal cortex on STM and LTM of a one-trial step-down inhibitory avoidance task was studied. The animals were tested at 1.5 h for STM, and again at 24 h for LTM. The treatments were given after training.3. Eleven different treatments blocked STM without affecting LTM. Eighteen treatments affected the two memory types differentially, either blocking or enhancing LTM alone. Thus, STM is separate from, and parallel to the first hours of processing of, LTM of that task.4. The mechanisms of STM are different from those of LTM. The former do not include gene expression or protein synthesis; the latter include a double peak of cAMP-dependent protein kinase activity, accompanied by the phosphorylation of CREB, and both gene expression and protein synthesis.5. Possible cellular and molecular events that do not require mRNA or protein synthesis should account for STM. These might include a hyperactivation of glutamate AMPA receptors, ribosome changes, or the exocytosis of glycoproteins that participate in cell addition.

Pharmacological demonstration of the differential involvement of protein kinase C isoforms in short- and long-term memory formation and retrieval of one-trial avoidance in rats

Abstract Rationale: The hippocampal protein kinase C (PKC) family is involved in the early events of consolidation of long-term potentiation (LTP) and long-term memory (LTM). Results so far are indecisive about which PKC isoform is involved and as to whether any of them plays a role in short-term memory (STM) processes, which have recently been shown to be separate from those of LTM in the hippocampus-dependent one-trial step-down inhibitory avoidance task. Objectives: To measure the effect of two PKC inhibitors, one (Gö 6976) selective to the calcium-dependent isoforms α and βI, and the other (Gö 7874) unspecific as to PKC isoforms on the formation and retrieval of STM and LTM of one-trial inhibitory avoidance. Methods: Rats bilaterally implanted with cannulae in the CA1 region of the dorsal hippocampus were trained in one-trial step-down inhibitory avoidance. The effect of these two drugs on STM and LTM formation was investigated as follows. Animals were infused 10 min before or 50, 110, or 170 min after inhibitory avoidance training with a vehicle (2% dimethylsulfoxide in saline), or with Gö 6976 (0.92 nM or 4.6 nM) or Gö 7874 (1.96 nM or 8 nM) dissolved in the vehicle. Infusion volume was 0.5 µl in all cases. Animals were tested 1.5 h and 3 h after training for STM and at 24 h for LTM. In order to study the effects of these compounds on retrieval, they were infused into the hippocampus 10 min prior to STM testing at 3 h (see above) or 10 min before LTM testing at 24 h. In addition, the effect of Gö 6976 and Gö 7874 was studied on general activity measured in an open field, and on performance in an elevated plus maze. Results: STM was suppressed by 4.6 nM Gö 6976 given 10 min before or 50 min after training. LTM was cancelled by the higher dose of the two compounds given 10 min before, or 50 min or 110 min after training. None of the two compounds infused 170 min post-training affected the retrieval of STM measured 10 min later. However, both compounds given 10 min before testing inhibited the retrieval of LTM measured at 24 h. This effect cannot be attributed to influences on locomotor activity or anxiety levels, since the drugs had no effect on performance in the open field but were mildly ”anxiogenic” (pro-conflict) and reduced the number of entries into open and closed arms and rearings. Conclusions: LTM consolidation requires in part α- and/or βI-PKC and in part other PKC isoforms. STM formation requires instead only α and/or βI-PKC and during a more limited period of time. In addition, PKC appears not to be necessary for the retrieval of STM, but is crucial for the retrieval of LTM. These findings further point to a biochemical separation of STM and LTM, as ascertained in numerous previous studies.

O índice de linfonodos comprometidos como um preditor para a ocorrência de recidivas tumorais no câncer de cólon estádio III

OBJETIVO: avaliar o indice de linfonodos comprometidos na ocorrencia de recidivas tumorais em pacientes com câncer de colon estadio III. METODOS: foram avaliados de maneira retrospectiva todos os pacientes com câncer de colon estadio III submetidos a resseccao curativa do tumor primario entre janeiro de 2005 e dezembro de 2010. Os desfechos de interesse foram a ocorrencia de recidivas tumorais e morte. O impacto do indice de linfonodos comprometidos e das demais variaveis clinico-patologicas na sobrevida livre de doenca foi avaliado atraves de analise uni e multivariavel. De modo a identificar-se o ponto de corte de maior acuracia para utilizacao do indice de linfonodos comprometidos como um preditor de recidivas tumorais realizou-se a analise da curva caracteristica de operacao do receptor. A sobrevida livre de doenca foi avaliada atraves de curvas de Kaplan-Meier. RESULTADOS: setenta pacientes foram incluidos no estudo (50% masculinos). A media de idade foi 64 anos. A analise univariavel identificou quatro fatores determinantes para a ocorrencia de recidivas tumorais: antigeno carcinoembrionario, estadiamento N, numero de linfonodos positivos e indice de linfonodos comprometidos. O indice de linfonodos comprometidos foi o que demonstrou a maior magnitude de associacao. A analise da curva caracteristica de operacao do receptor identificou 0,15 como o ponto de corte ideal. Pacientes com um indice de linfonodos comprometidos <0,15 apresentavam uma sobrevida livre de doenca de 90% em tres anos (versus 64%, P=0,011). CONCLUSAO: o indice de linfonodos comprometidos e um forte preditor para recidivas tumorais no câncer de colon estadio III.

Morphine does no promote esophageal carcinogenesis in rats exposed to diethylnitrosamine

BACKGROUND The high incidence of esophageal cancer in the north of Iran has been associated to the consumption of opium and exposure to nitrosamines. Diethylnitrosamine has an established potential of producing experimental cancer in the esophagus and liver. AIM To evaluate by histopathology the effect of oral administration of morphine and diethylnitrosamine during 23 weeks on the hepatic and esophageal carcinogenesis on 176 rats. METHODS We divided the rats into the following groups: Morph: morphine; Den: diethylnitrosamine; Den+morph: Den and morphine in the same solution; Den/morph: Den and morphine in different solutions and days. RESULTS Morphine did not promote neoplasias. The highest neoplastic incidents were found: a) in the esophagus, Den in relation to Den/morph and Den+morph (71.1%, 55.8%, and 50.0%); b) in the liver, Den and Den/morph in relation to Den+morph (73.8%, 81.4%, and 40.9%); c) higher incident of hepatic neoplasia than esophageal in Den/morph (81.4% and 55.8%). Different doses of diethylnitrosamine were ingested among the groups Den, Den/morph, and Den+morph, respectively 2.9, 2.8, and 2.3 mg/kg/day. CONCLUSIONS These results show that the morphine did not promote esophageal carcinogenesis and may have stimulated the hepatic metabolism of the first pass of the carcinogen.