Subcommissural organ-Reissner's fiber complex plasticity in two animal models of copper intoxication and modulatory effect of curcumin: Involvement of serotonin.

Metal neurotoxicity is a universal health preoccupation. Previous data revealed an obvious neurochemical impairment induced by metal elements as copper. This investigation was conducted to study the subcommissural organ (SCO) response to acute and subchronic Cu exposure as well as its serotoninergic innervation in Wistar rats, and the probable protective potential of curcumin in these toxicological circumstances. By mean of immunohistochemistry using antibodies against Reissner's fiber (RF) and serotonin (5-HT) in acute model (10 mg/kg i.p. for 3 days) and subchronic model (0.125% in drinking water for six weeks), we noted a significant decrease of RF-immunoreactivity and a whole amplified 5-HT innervation of SCO and ventricular borders in intoxicated rats. Co-treatment with curcumin-I (30 mg/kg B.W) has shown a beneficial effect, reinstating both SCO secretory activity and serotoninergic innervation damaged by Cu exposure. This data revealed for the first time an obvious response of SCO-RF complex to Cu intoxication as well as the neuroprotective effect of curcumin-I. Thus, SCO could play a fundamental role in the strategies of brain resistance to neurotoxicity induced by metal elements in rats, and may be used as biomarker to assist in the diagnosis of this neurotoxicological conditions in rodents.

Neuroprotective effects of docosahexaenoic acid against sub-acute manganese intoxication induced dopaminergic and motor disorders in mice.

Manganese (Mn) is an essential metallic trace element involved in several vital biological functions. Conversely, exposure to excessive levels of Mn induces manganism, causing neurodegeneration and symptoms similar to those seen in Parkinson's disease (PD). Docosahexaenoic acid (DHA) is a long-chain polyunsaturated fatty acid exhibiting neuroprotective properties against neurodegenerative diseases and brain injuries and is known to easily incorporate into membrane phospholipids of brain cells and meditates its corrective actions. In the present study, mice were used for a sub-acute Mn intoxication model to investigate DHA neuroprotective potential against Mn neurotoxicity. We also seek to understand the mechanism by which Mn intoxication induces these motor impairments at 30 mg/kg, by pretreatment with DHA at 200 mg/kg and assessment of changes in spontaneous locomotor behavior by open field test (OF), motor coordination using the rotarod test (RR) and strength by mean of weights test (WT). To highlight these effects on brain neurotransmission, we evaluated the tyrosine hydroxylase immunoreactivity (TH-IR) within substantia nigra compacta (SNC) and striatum (St). Results showed that Mn intoxication significantly altered motor behavior parameters including, decreased of traveled distance by 46%, decreased mean speed by 36%, reduced the ability to sustain the rotarod test to 42%; Moreover, a drop score was obtained using weights test and reflecting affected strength in Mn-intoxicated animals. Pretreatment by DHA prevents mice from Mn toxicity and maintain normal spontaneous activity, motor coordination and strength. Data also showed the ability of Mn to disrupt dopamine neurotransmission by altering tyrosine hydroxylase activity in the nigrostriatal pathway while in pretreated animals, DHA prevented this disruption. Data approved the potential neurotoxic effect of Mn as a risk factor of the Parkinsonism onset, and then demonstrated for the first time the neuroprotective and nutraceutical outcomes of DHA in the sub-acute Mn-intoxication animal model.

Kinetic deterioration of short memory in rat with acute hepatic encephalopathy: Involvement of astroglial and neuronal dysfunctions.

Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome resulting from acute or chronic hepatic impairments. The clinical features of HE include attention as well as a mild cognitive deficits associated with impaired attentional and executive networks in patients as well as in animal models of HE. The underlining pathomechanism of memory impairment in HE patients is still not fully understood; however, it may involve a possible gliopathy as well as neuropathy. The aim of the present investigation is to assess progression of short working memory deterioration in acute HE and to delineate the glial and the neuronal alteration which may underlie such cognitive impairment. The study was carried out in male Sprague-Dawley rats with acute liver failure induced by thioacetamide (TAA). The study was performed on different stages of acute HE; 12 h, 24 h and 36 h following administration of TAA. The liver functions were assessed via different biochemical markers (ALT, AST, bilirubin, urea and creatinine) and an histopathological examination of the liver tissue. While for the behavioral study, we used T-Maze test to assess short working memory using the percentage of alternation behavior, together with an immunohistochemical analysis of the Glial Fibrillary Acidic Protein (GFAP) as the key marker of astrocytes in the hippocampus, as well as serotonin (5-HT) for 5-HTergic neurons within the dorsal Raphe nucleus (DRN). Our data revealed a progressive loss of liver tissue integrity with inflammation and hepatocytes degeneration which was associated to obvious loss of the liver function. In parallel, we observed a gradual alteration of the alternation behavior, as a sign of altered short working memory in the acute HE rats. At the central level, the immunohistochemical study showed a time dependent region-specific changes of GFAP-immunoreactive astrocytes within the hippocampus. While within the DRN, serotonin levels declined progressively in a time-dependant manner. Our data revealed for the first time, a gradual loss of short memory function in acute HE, resulting from liver dysfunction. Such cognitive deterioration may involve a possible gliopathy as well as a 5-HTergic dysfunction which could be considered as a new key element for understanding the basis of memory and attention loss in HE patients.

Differential impairment of short working and spatial memories in a rat model of progressive Parkinson's disease onset: A focus on the prodromal stage.

Studying the non-motor disorders of the prodromal phase of Parkinson's disease (PD) is of great importance because of their negative impact on patient's quality of life. Classical neurotoxic animal models of PD generally unable the exploration of the progression of the non-motor phase of the prodromal stage of the disease. The aim of this study is to assess the evolution of two types of memory alteration namely; short working and spatial memories at different stages of the prodromal phase of a rat model of PD, using repetitive reserpine administration at low dose. The study was carried out in rat with repeated i.p reserpine administration (0.2 mg/kg/day) during 13 days. Working memory was assessed by the Novel Object Recognition test (NOR) and the T-maze, while spatial memory was assessed by Morris Water maze (MWM) at to stages (7days and 13days) of prodromal phase of the disease. By means of immunohistochemistry, the serotonergic innervation of the Baso-Lateral Amygdala nucleus (BLA) as well as the morphological changes of astroglia within hippocampus (using anti-GFAP marker) were examined at the latest stage (13days) of the disease. Our data show a differential deterioration of short-term working memory without the long-term spatial memory being changed which was accompanied by a significant decrease in serotonin innervation of the BLA and a striking change in both density and morphology of the astrocyte at the level of the hippocampus. The present study has brought evidence of an early deficit of short working memory rather than spatial memory deficit which seems to be intact even at the latest stage of the prodromal phase of PD. Such deficit could arise from the loss of 5-HT innervation in BLA and/or the astroglial morpho-functional changes within the hippocampus leading to possible neurophysiological disturbances of the different neighboring neuronal populations involved in short working memory.