Alessandra D'Amico

The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-β peptide-induced neurotoxicity

Traditional use and clinical reports suggest that the culinary herb sage (Salvia officinalis) may be effective for patients with mild to moderate Alzheimers disease (AD). In this study, we evaluated the effect of a standardized extract from the leaves of S. officinalis (SOE) and its active ingredient rosmarinic acid on Alzheimer amyloid-β peptide (Aβ)-induced toxicity in cultured rat pheochromocytoma (PC12) cells. Incubation of PC12 cells with Aβ (fragment 1–42) for 24 h caused cell death, and this effect was reduced by SOE and its active ingredient, rosmarinic acid. Rosmarinic acid reduced a number of events induced by Aβ. These include reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation, and tau protein hyperphosphorylation. Moreover, rosmarinic acid inhibited phosphorylated p38 mitogen-activated protein kinase but not glycogen synthase kinase 3β activation. These data show the neuroprotective effect of sage against Aβ-induced toxicity, which could validate the traditional use of this spice in the treatment of AD. Rosmarinic acid could contribute, at least in part, for sage-induced neuroprotective effect.

The diverse phenotype and genotype of pantothenate kinase-associated neurodegeneration

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare autosomal-recessive disorder caused by mutations in the PANK2 gene. The authors report clinical and genetic findings of 16 patients with PKAN. The authors identified 12 mutations in the PANK2 gene, five of which were new. Only nine patients could be classified as classic or atypical PKAN, and intermediate phenotypes are described. Two patients presented with motor tics and obsessive-compulsive behavior suggestive of Tourette syndrome.

Effect of cannabidiol on sepsis‐induced motility disturbances in mice: involvement of CB1 receptors and fatty acid amide hydrolase

Abstractu2002 Sepsis is an inflammatory condition that is associated with reduced propulsive gastrointestinal motility (ileus). A therapeutic option to treat sepsis is to promote intestinal propulsion preventing bacterial stasis, overgrowth and translocation. Recent evidence suggests that anti‐oxidants improve sepsis‐induced ileus. Cannabidiol, a non‐psychotropic component of Cannabis sativa, exerts strong anti‐oxidant and anti‐inflammatory effects without binding to cannabinoid CB1 or CB2 receptors. Cannabidiol also regulates the activity of fatty acid amide hydrolase (FAAH) which is the main enzyme involved in endocannabinoid breakdown and which modulates gastrointestinal motility. Because of the therapeutic potential of cannabidiol in several pathologies, we investigated its effect on sepsis‐induced ileus and on cannabinoid receptor and FAAH expression in the mouse intestine. Sepsis was induced by treating mice with lipopolysaccharides for 18u2003h. Sepsis led to a decrease in gastric emptying and intestinal transit. Cannabidiol further reduced gastrointestinal motility in septic mice but did not affect gastrointestinal motility in control mice. A low concentration of the CB1 antagonist AM251 did not affect gastrointestinal motility in control mice but reversed the effect of cannabidiol in septic mice. Sepsis was associated with a selective upregulation of intestinal CB1 receptors without affecting CB2 receptor expression and with increased FAAH expression. The increase in FAAH expression was completely reversed by cannabidiol but not affected by AM251. Our results show that sepsis leads to an imbalance of the endocannabinoid system in the mouse intestine. Despite its proven anti‐oxidant and anti‐inflammatory properties, cannabidiol may be of limited use for the treatment of sepsis‐induced ileus.

The Levels of the Endocannabinoid Receptor CB2 and Its Ligand 2-Arachidonoylglycerol Are Elevated in Endometrial Carcinoma

The endocannabinoid system plays protective roles against the growth and the spreading of several types of carcinomas. Because estrogens regulate this system both in physiological states and cancer, in this paper we evaluated its involvement in endometrial carcinoma, a well-known estrogen-dependent tumor. To test whether the endocannabinoid system is expressed in endometrial cancer, tissue samples were collected both from 18 patients undergoing surgical treatment for endometrial adenocarcinoma and 16 healthy age-matched controls, and treated for Western blot and immunohistochemical analysis. Moreover, tissues were dounce homogenized and submitted to endocannabinoid measurement by liquid chromatography-mass spectrometry. To evaluate the physiological role of the endocannabinoid system, a human endometrial cancer cell-line (AN3CA) was used and transiently transfected with a plasmid containing the cDNA for the endocannabinoid receptor CB(2). Cells were incubated for 48 h with an agonist (JWH133) (10 mum) or antagonist (SR144528) (1 mum) of CB(2) 24 h after transfection, and cell proliferation was measured by the 3-[4,5-dimethyltiazol-2yl]-2,5 diphenyltetrazolium bromide formazan assay. In human endometrial carcinoma biopsies the expression of CB(2) receptor and the levels of its ligand, 2-arachidonoylglycerol increased, whereas monoacylglycerol lipase, an enzyme responsible for 2-arachidonoylglycerol degradation, was down-regulated. Immunohistochemical analysis revealed that CB(2) was overexpressed only in malignant endometrial cells. CB(2)-overexpressing AN3CA cells showed a significant reduction in cell vitality compared with parental AN3CA cells: incubation with the selective CB(2) antagonist SR144128 restored the viability of CB(2)-overexpressing cells to that of untransfected cells. In conclusion, the endocannabinoid system seems to play an important role in human endometrial carcinoma, and modulation of CB(2) activity/expression may account for a tumor-suppressive effect.

Selective CB2 up-regulation in women affected by endometrial inflammation

Endometritis is defined as an inflammation of the endometrial mucosa of the uterus. In endometritis large amounts of toxic mediators, including nitric oxide (NO) are released by inflammatory cells. As a consequence of nitric oxide‐dependent injury, the cells respond by triggering protective mechanisms, by changing the endo‐cannabinoid system (ECS) which comprises both CB1 and CB2 cannabinoid receptors and their endogenous ligands. The aim of our study was to seek out evidence for the presence of cannabinoid receptors in inflammatory endometrial tissue as well as for their potential role in endometrial inflammation. Our results showed a selective up‐regulation of both transcription and expression of CB2 receptors in biopsies from women affected by endometrial inflammation compared to healthy women. The experiments with the nitric oxide‐donor S‐Nitroso‐L‐Glutathione (GSNO) suggest that such a selective up‐regulation may be related to the nitric oxide release occurring during endometrial inflammation. In addition, we demonstrated an increase in chymase expression, a marker of mast cells, in biopsies of women affected by endometritis. Therefore our results support the hypothesis that the up‐regulation of CB2 occurs mainly on mast cells and that it might tend to sensitize these cells to the anti‐inflammatory effect exerted by endogenous cannabinoids by binding their receptor and thus preventing the mast cell degranulation and the release of pro‐inflammatory mediators. In conclusion, we believe that the selective CB2 up‐regulation might play a role as a novel prognostic factor in endometrial inflammation.

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst

The immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome is an autosomal recessive disease presenting with immunodeficiency secondary to hypo‐ or agamma‐globulinemia, developmental delay, and facial anomalies. Centromeric instability is the cytogenetic hallmark of the disorder which results from targeted chromosomal rearrangements related to a genomic methylation defect. We describe a patient carrying a homozygous mutation of the ZBTB24 gene, which has been recently shown to be responsible for ICF syndrome type 2. Our patient presented with intellectual disability, multiple café‐au‐lait spots, and a large cerebral arachnoidal cyst. Although laboratory signs of impaired immune function, such as reduced serum IgM were detected, our patient did not present clinical manifestations of immunodeficiency. Brain malformations abnormalities have not been reported so far in ICF syndrome and it can be speculated that ZBTB24 mutations may alter cerebral development. Nevertheless, we cannot rule out that the presence of the cerebral cyst in the patient is coincidental. In summary, our patient illustrates that clinical evidence of immunodeficiency is not a universal feature of ICF2 syndrome type 2 and suggests that brain malformations may be present in other ICF cases.

A further contribution to the delineation of the 17q21.31 microdeletion syndrome: Central nervous involvement in two Italian patients

The 17q21.31 microdeletion syndrome is a genetic disorder characterized by intellectual disability, facial dysmorphisms and a typical behavioral phenotype. Patients are usually described as friendly and cooperative but they can also show behavioral problems such as hyperactivity, bad humor, temper tantrums and poor interaction. Central nervous system involvement includes callosal dysgenesis/absence, enlargement of lateral ventricles and abnormalities of cyngulate gyrus. We report on two Italian patients with the 17q21.31 microdeletion syndrome better emphasizing neuroimaging and neuropsychological characteristics. In particular, we carried out an assessment of intellectual efficiency and behavior that turned out to be within the mild-moderate range of mental retardation, as already reported in the literature. To the best of our knowledge this is the first report of a patient with the 17q21.31 microdeletion and a Chiari malformation type 1 coexisting with a mild anomaly of medulla oblongata. This malformation should be considered in patients with the 17q21.31 microdeletion syndrome, presenting suggestive symptoms (headache, neck pain, cerebellar signs or muscle weakness).

Differential Cannabinoid Receptor Expression during Reactive Gliosis: a Possible Implication for a Nonpsychotropic Neuroprotection

Activated microglia and astrocytes produce a large number of inflammatory and neurotoxic substances in various brain pathologies, above all during neurodegenerative disorders. In the search for new neuroprotective compounds, interest has turned to marijuana derivatives, since in several in vitro, in vivo, and clinical studies, they have shown a great ability to control neuroinflammation. Despite the emerging evidence regarding pharmacological activities of cannabinoids, their effective introduction into clinical therapy still remains controversial and strongly limited by their unavoidable psychotropicity. Since the psychotropic effect of cannabinoids is generally linked to the activation of the CB1 receptor on neurons, the aim of our review is to clarify the function of the two cannabinoid receptors on glial cells and the differential role played by them, highlighting the emerging evidence of a CB2-mediated control of neuroinflammation that could liberate cannabinoids from the slavery of their central side effects.

Pure unilateral hyperhidrosis after pontine infarct

Sweating abnormalities, often masked by other neurologic deficits, have been infrequently described in patients after brainstem infarctions.1,2⇓ Pontine and medullary strokes may produce transient contralateral hyperhidrosis, attributed to a lesion of the putative sympathoinhibitory tract, which controls sweating of the contralateral side of the body.1 A precise clinicoanatomic correlation between pontine lesions and hyperhidrosis has not been reported to date because the described lesions usually involved large areas of the brainstem, producing complex clinical pictures.2-5⇓⇓⇓nnWe describe a patient with pure persistent hemihyperhidrosis secondary to a small lacunar stroke of the contralateral upper pons.nnA 72-year old woman was examined after complaining of abnormal sweating on the right side of her body. This symptom acutely appeared 5 years before in the absence of other signs of neurologic involvement. It persisted during the years, although occurring less frequently than during the first months. It was elicited by heat exposure, effort, and stress.nnShe had no hypertension, diabetes, smoking, or …

Moyamoya syndrome in children with neurofibromatosis type 1: Italian-French experience

Moyamoya syndrome (MMS) is the most common cerebral vasculopathy among children with neurofibromatosis type 1 (NF1). In this study, we clinically, radiologically, and genetically examined a cohort that was not previously described, comprising European children with NF1 and MMS. The NF1 genotyping had been registered. This study included 18 children. The mean age was 2.93u2009±u20093.03 years at the NF1 diagnosis and 7.43u2009±u20094.27 years at the MMS diagnosis. In seven patients, MMS was diagnosed before or at the same time as NF1. Neuroimaging was performed in 10 patients due to clinical symptoms, including headache (nu2009=u20096), cerebral infarction (nu2009=u20092), and complex partial seizures (nu2009=u20092). The remaining eight children (47%) had MMS diagnosed incidentally. Sixteen children were characterized molecularly. The features of MMS were similar between patients with and without NF1. Additionally, the NF1 phenotype and genotype were similar between children with and without MMS. Interestingly, three children experienced tumors with malignant histology or behavior. The presence of two first cousins in our cohort suggested that there may be potential genetic factors, not linked to NF1, with an additional role respect of NF1 might play a role in MMS pathogenesis. The incidental diagnosis of MMS, and the observation that, among children with NF1, those with MMS were clinically indistinguishable from those without MMS, suggested that it might be worthwhile to add an angiographic sequence to brain MRIs requested for children with NF1. A MMS diagnosis may assist in properly addressing an NF1 diagnosis in very young children who do not fulfill diagnostic criteria.