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Neuroimaging studies have demonstrated gray matter (GM) volume abnormalities in substance users. While the majority of substance users are polysubstance users, very little is known about the relation between GM volume abnormalities and polysubstance use.In this study we assessed the relation between GM volume, and the use of alcohol, tobacco, cocaine and cannabis as well as the total number of substances used, in a sample of 169 males: 15 non-substance users, 89 moderate drinkers, 27 moderate drinkers who also smoke tobacco, 13 moderate drinkers who also smoke tobacco and use cocaine, 10 heavy drinkers who smoke tobacco and use cocaine and 15 heavy drinkers who smoke tobacco, cannabis and use cocaine.Regression analyses showed that there was a negative relation between the number of substances used and volume of the dorsal medial prefrontal cortex (mPFC) and the ventral mPFC. Without controlling for the use of other substances, the volume of the dorsal mPFC was negatively associated with the use of alcohol, tobacco, and cocaine. After controlling for the use of other substances, a negative relation was found between tobacco and cocaine and volume of the thalami and ventrolateral PFC, respectively.These findings indicate that mPFC alterations may not be substance-specific, but rather related to the number of substances used, whereas, thalamic and ventrolateral PFC pathology is specifically associated with tobacco and cocaine use, respectively. These findings are important, as the differential alterations in GM volume may underlie different cognitive deficits associated with substance use disorders.

We examined the effect of chronic prenatal alcohol exposure (PAE) on the process of adult neurogenesis in C57BL/6J mice at early adulthood (PND 56). Pregnant mice, and their in utero litters, were exposed to alcohol, through oral gavage, on gestational days 7-16, with recorded blood alcohol concentrations averaging 184 mg/dL (CA group). Two control groups, sucrose (CAc) and non-treated (NTc) control groups were also examined. The brains of pups at PND 56 from each experimental group were sectioned in a sagittal plane, and stained for Nissl substance with cresyl violet, and immunostained for Ki-67 which labels proliferative cells and doublecortin (DCX) for immature neurons. Morphologically, the neurogenic pattern was identical in all three groups studied. Populations of Ki-67 immunopositive cells in the dentate gyrus were not statistically significantly different between the experimental groups and there were no differences between the sexes. Thus, the PAE in this study does not appear to have a strong effect on the proliferative process in the adult hippocampus. In contrast, the numbers of immature neurons, labeled with DCX, was statistically significantly lower in the prenatal alcohol exposed mice compared with the two control groups. Alcohol significantly lowered the number of DCX hippocampal cells in the male mice, but not in the female mice. This indicates that the PAE appears to lower the rate of conversion of proliferative cells to immature neurons and this effect of alcohol is sexually dimorphic. This lowered number of immature neurons in the hippocampus appears to mirror hippocampal dysfunctions observed in FASD children.

Chronic ethanol exposure causes neurotoxicity and long-term learning and memory impairment along with hippocampal and frontal cortical dysfunction. Flavonoids possess antioxidant and anti-inflammatory properties believed to be contributory factors in reversing cognitive decline. 6-Methoxyflavone (6-MOF), a flavonoid occurring naturally in medicinal plants, has been reported to instigate neuroprotection by reversing cisplatin-induced hyperalgesia and allodynia. Consequently, this study was designed to investigate 6-MOF activity in models of chronic ethanol-induced cognitive impairment along with neurochemical correlates.Mice were given ethanol orally (2.0 g/kg daily) for 24 days plus either saline, 6-MOF (25-75mg/kg) or donepezil (4mg/kg) and then ethanol was withdrawn for the next 6 days. Animals were subsequently assessed for their cognitive performance in several models on days 1, 12, and 24, during abstinence (Day-26) and on the 7th day of the washout period. Following behavioral assessment, post-mortem dopamine, noradrenaline and vitamin C concentrations were quantified in the frontal cortex, hippocampus and striatum, using HPLC with UV detection.Chronic ethanol treatment suppressed locomotor activity and impaired cognitive tasks, which included novel object recognition, performance in the Morris water maze as well as the Y-maze, socialization and nest-building behavior throughout the protocol and during withdrawal. These behavioral deficits were at least partially restored by the co-administration of 6-MOF or donepezil with ethanol as were ethanol-induced deficits in frontal cortical and hippocampal dopamine plus noradrenaline, together with striatal dopamine. 6-MOF co-administration with ethanol also modestly restored striatal vitamin C levels.It is postulated that, apart from donepezil, 6-MOF may be useful not only in the treatment of ethanol withdrawal severity but also in the management of chronic ethanol withdrawal induced cognitive impairment.

The consequences of alcohol drinking during pregnancy are dramatic and usually referred to as fetal alcohol spectrum disorders (FASD). This condition is one of the main causes of intellectual disability in Western countries. The immature fetal brain exposed to ethanol undergoes massive neuron death. However, the same mechanisms leading to cell death can also be responsible for changes of developmental plasticity. As a consequence of such a maladaptive plasticity, the functional damage to central nervous system structures is amplified and leads to permanent sequelae. Here we review the literature dealing with experimental FASD, focusing on the alterations of the cerebral cortex. We propose that the reciprocal interaction between cell death and maladaptive plasticity represents the main pathogenetic mechanism of the alcohol-induced damage to the developing brain.

We report two cases of acute haematogenous osteomyelitis in the anterior superior iliac spine (ASIS) in adolescent goalkeepers following trauma of the iliac crest apophysis. Both patients complained of pain over their right ASIS and were pyrexial. They were given antibiotics and were discharged from follow up without complication 64 and 90 days after starting treatment.

In Canada, the use of botanical natural health products (NHPs) for anxiety disorders is on the rise, and a critical evaluation of their safety and efficacy is required. The purpose of this study was to determine whether commercially available botanicals directly affect the primary brain enzymes responsible for γ-aminobutyric acid (GABA) metabolism. Anxiolytic plants may interact with either glutamic acid decarboxylase (GAD) or GABA transaminase (GABA-T) and ultimately influence brain GABA levels and neurotransmission. Two in vitro rat brain homogenate assays were developed to determine the inhibitory concentrations (IC50) of aqueous and ethanolic plant extracts. Approximately 70% of all extracts that were tested showed little or no inhibitory effect (IC50 values greater than 1 mg/mL) and are therefore unlikely to affect GABA metabolism as tested. The aqueous extract of Melissa officinalis (lemon balm) exhibited the greatest inhibition of GABA-T activity (IC50 = 0.35 mg/mL). Extracts from Centella asiatica (gotu kola) and Valeriana officinalis (valerian) stimulated GAD activity by over 40% at a dose of 1 mg/mL. On the other hand, both Matricaria recutita (German chamomile) and Humulus lupulus (hops) showed significant inhibition of GAD activity (0.11–0.65 mg/mL). Several of these species may therefore warrant further pharmacological investigation. The relation between enzyme activity and possible in vivo mode of action is discussed.

Melatonin is a well-known potent endogenous antioxidant pharmacological agent with significant neuroprotective actions. Here in the current study, we explored the nuclear factor erythroid 2-related factor 2 (Nrf2) gene-dependent antioxidant mechanism underlying the neuroprotective effects of the acute melatonin against acute ethanol-induced elevated reactive oxygen species (ROS)-mediated neuroinflammation and neurodegeneration in the developing rodent brain.In vivo rat pups were co-treated with a single dose of acute ethanol (5 g/kg, subcutaneous (S.C.)) and a single dose of acute melatonin (20 mg/kg, intraperitoneal (I.P.)). Four hours after a single S.C. and I.P. injections, all of the rat pups were sacrificed for further biochemical (Western blotting, ROS- assay, LPO-assay, and immunohistochemical) analyses. In order to corroborate the in vivo results, we used the in vitro murine-hippocampal HT22 and microglial BV2 cells, which were subjected to knockdown with small interfering RNA (siRNA) of Nrf2 genes and exposed with melatonin (100 μM) and ethanol (100 mM) and proceed for further biochemical analyses.Our biochemical, immunohistochemical, and immunofluorescence results demonstrate that acute melatonin significantly upregulated the master endogenous antioxidant Nrf2 and heme oxygenase-1, consequently reversing the acute ethanol-induced elevated ROS and oxidative stress in the developing rodent brain, and in the murine-hippocampal HT22 and microglial BV2 cells. In addition, acute melatonin subsequently reduced the activated MAPK-p-P38-JNK pathways and attenuated neuroinflammation by decreasing the expression of activated gliosis and downregulated the p-NF-K-B/p-IKKβ pathway and decreased the expression levels of other inflammatory markers in the developing rodent brain and BV2 cells. Of note, melatonin acted through the Nrf2-dependent mechanism to attenuate neuronal apoptosis in the postnatal rodent brain and HT22 cells. Immunohistofluorescence results also showed that melatonin prevented ethanol-induced neurodegeneration in the developing rodent brain. The in vitro results indicated that melatonin induced neuroprotection via Nrf2-dependent manner and reduced ethanol-induced neurotoxicity.The pleiotropic and potent neuroprotective antioxidant characteristics of melatonin, together with our in vivo and in vitro findings, suppose that acute melatonin could be beneficial to prevent and combat the acute ethanol-induced neurotoxic effects, such as elevated ROS, neuroinflammation, and neurodegeneration in the developing rodent brain.