The dose-dependent neuroprotective effect of norepinephrine in improving memory retrieval in an experimental model of multiple sclerosis, experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is considered an immune-mediated inflammatory disorder that causes cognitive impairments by damaging the hippocampal tissue. Conversely, norepinephrine (NEP) has anti-inflammatory and re-myelinating properties, which improve cognitive impairments. The aim of this study was to assess the neuroprotective effects of NEP on learning and memory disorders in an experimental animal model of MS. Two guide cannulas were bilaterally implanted in the rat hippocampal CA1 regions. After recovery, the animals received 3 µl of 0.01% ethidium bromide (EtB) in each of both hippocampal regions. After three days, the rats were randomly divided into 6 groups (8 rats/group), including control, sham 1, sham 2, and three groups of NEP 0.25, 0.5, and 1 mg/kg by intrahippocampal injection. Behavioral tests (e.g. shuttle box test and open-field test) were then performed. Finally, ROS, MDA, GSH, TNF-α, IL-6, and IL-1ß concentrations in the left CA1 area, as well as using western-blot analysis, p-p38, p-JNK, p-AKT, p-ERK1/2, p-NMDA, p-AMPA, p-CREB, and BDNF proteins in the right CA1 region evaluated. The EtB injection increased ROS, MDA, TNF-α, IL-6, and IL-1ß levels, as well as p-JNK and p-P38, except all other proteins, while decreasing GSH content, as well as step-through latency and locomotor activity in sham groups compared to the control group. Conversely, NEP (0.5 and 1 mg/kg, particularly at the dose of 1 mg/kg) counterbalanced all the alterations mentioned above in comparison to the sham groups. The EtB induced learning and memory impairment; however, NEP dose-dependently restored these impairments to normal levels.

Vitamin B12 and estradiol benzoate improve memory retrieval through activation of the hippocampal AKT, BDNF, and CREB proteins in a rat model of multiple sclerosis.

OBJECTIVES: Multiple sclerosis (MS) causes extensive damage in the hippocampus. Vitamin B12 (vit B12) and estradiol benzoate (EB) have anti-inflammatory and re-myelination properties that make them proper in improvement of cognitive impairment. This study aimed to evaluate the effects of these compounds on learning and memory disturbances. MATERIALS AND METHODS: 77 adult male rats were implanted with stainless steel guide cannula bilaterally into the hippocampal area. The animals received 3 µl intrahippocampal EtB 0.01% and were randomly divided into eleven groups (7 rats/group). The groups included control, peanut oil (sham1), distilled water (sham 2), vit B12 (0.25, 0.5, 1 mg/kg), EB (25 and 50 mg/kg), vit B12 (0.25 mg/kg) plus EB (25 mg/kg), vit B12 (0.5 mg/kg) plus EB (25 mg/kg), and vit B12 (1 mg/kg) plus EB (50 mg/kg). The control group received intrahippocampal saline (as solvent). The locomotor activity and learning and memory functions were evaluated by open-field and shuttle-box tests, respectively. AKT, CREB, and BDNF levels were analyzed by Western blotting. RESULTS: This study has found significant deficit in passive avoidance learning, locomotor activity, as well as decrease in the levels of phosphorylated AKT, BDNF, and CREB in groups that received EtB. Vit B12 (1 mg/kg), EB (50 mg/kg), and their combination markedly improved these side effects. CONCLUSION: This study demonstrated that vit B12 and estradiol benzoate, especially in combination therapy, can be helpful in treatment of memory problems and MS-induced dysfunction through activation of the hippocampal AKT, BDNF, and CREB proteins.