Olea Europea-derived phenolic products attenuate antinociceptive morphine tolerance: an innovative strategic approach to treat cancer pain.

Morphine and related opioid drugs are currently the major drugs for severe pain. Their clinical utility is limited in the management of severe cancer pain due to the rapid development of tolerance. Restoring opioid efficacy is therefore of great clinical importance. A great body of evidence suggests the key role of free radicals and posttranslational modulation in the development of tolerance to the analgesic activity of morphine. Epidemiological studies have shown a relationship between the Mediterranean diet and a reduced incidence of pathologies such as coronary heart disease and cancer. A central hallmark of this diet is the high consumption of virgin olive oil as the main source of fat which contains antioxidant components in the non-saponifiable fraction, including phenolic compounds absent in seed oils. Here, we show that in a rodent model of opiate tolerance, removal of the free radicals with phenolic compounds of olive oil such as hydroxytyrosol and oleuropein reinstates the analgesic action of morphine. Chronic injection of morphine in mice led to the development of tolerance and this was associated with increased nitrotyrosin and malondialdehyde (MDA) formation together with nitration and deactivation of MnSOD in the spinal cord. Removal of free radicals by hydroxytyrosol and oleuropein blocked morphine tolerance by inhibiting nitration and MDA formation and replacing the MnSOD activity. The phenolic fraction of virgin olive oil exerts antioxidant activities in vivo and free radicals generation occurring during chronic morphine administration play a crucial role in the development of opioid tolerance. Our data suggest novel therapeutic approach in the management of chronic cancer pain, in particular for those patients who require long-term opioid treatment for pain relief without development of tolerance.

Effect of MN (III) tetrakis (4-benzoic acid) porphyrin by photodynamically generated free radicals on SODs keratinocytes.

Superoxide, a reactive form of oxygen, can be produced in vivo either in normal and under pathophysiologic conditions or by photosensitizing chemicals, as during photodynamic treatment. Photodynamic therapies (PDT), widely adopted in Dermatology and Oncology, are known to generate reactive oxygen species (ROS) and may contribute to structural alterations and oxidatively generated modifications of cellular antioxidants. We hypothesized that over-production of free radicals would decrease the enzymatic activities of endogenous cellular antioxidants. To test this hypothesis, keratinocytes were treated with the photosensitizer Photofrin plus visible light to produce free radicals and CuZnSOD and MnSOD activities were measured. Photodynamic treatment of keratinocytes increases malonylaldehyde production, nitrotyrosine staining and superoxide production. The enzymatic activities of CuZnSOD and MnSOD were significantly decreased after Photofrin plus visible light treatment. Our results suggest that the main cellular antioxidant system can be inactivated by photodynamically generated ROS. Pretreatment of keratinocytes with free radicals scavenger such as Mn (III) tetrakis (4-benzoic acid) porphyrin (MnTBAP) was able to restore the endogenous antioxidant system activities, inhibiting the MDA formation, nitrotyrosine staining and superoxide formation. Antioxidant therapy could therefore be a useful tool in protecting healthy epidermal cells against common side effects induced by antitumor targeted therapies.

Morphophenotype of medulloblastoma in children and adults. The size of nuclei.

OBJECTIVE: Uniform cells with round, regular nuclei characterize the typical histologic aspect of medulloblastoma. Enlargement of nuclei distinguishes the large-cell medulloblastoma variant and is associated with a poor prognosis in pediatric medulloblastomas. The aim of the present study was to compare the size of nuclei between pediatric and adult medulloblastomas by a morphometric analysis. MATERIAL AND METHODS: In 79 neurosurgical specimens of cerebellar medulloblastomas, the maximum nuclear diameter of the largest nuclei was measured. Measurements were performed with a digital-image analysis system. The measure of the maximum diameter was chosen in order to reduce the split cell error. RESULTS: The difference between the mean values in children and adults was statistically significant (p = 0,001). The distribution of maximum values measured in each case had two distinct peaks in the two age groups, in 3.5% of adult cases and in more than 30% of pediatric cases the maximum nuclear size was superior to 12 microm. CONCLUSIONS: The present results show that nuclei of tumor cells in pediatric medulloblastomas are larger than those in adult medulloblastomas and confirm that the phenotype of medulloblastoma is different in the two age groups. Distinct genetic events can, thus, underlie medulloblastoma in childhood and adult age, the prognostic role of genetic variables can differ by age.