Valproate and sodium butyrate attenuate manganese-decreased locomotor activity and astrocytic glutamate transporters expression in mice

Abstract

Manganese (Mn) is an essential trace element, but chronic overexposure to this metal, either environmentally or occupationally may cause manganism, a disease analogous to Parkinson’s disease. Inhibitors of histone deacetylases, such as valproic acid (VPA) and sodium butyrate (NaB) exert neuroprotective effects in various animal models of neurological disorders. Thus, the present study investigated whether VPA or NaB prevent Mn-induced neurotoxicity by assessing locomotor activities and expression of astrocytic glutamate transporters, glutamate transporter 1 (GLT-1) and glutamate aspartate transporter (GLAST), in C57BL/6 mice. C57BL/6 mice were pretreated with VPA (200 mg/kg, i.p.) or NaB (1200 mg/kg, i.p.) prior to intranasal instillation of Mn (30 mg/kg) continually for 21 days, followed by open-field and rota-rod behavioral tests and analyses of astrocytic glutamate transporters GLT-1 and GLAST protein/mRNA levels. The results showed that Mn significantly decreased locomotor activity as determined by total distance travelled, stereotypic and ambulatory counts. Mn also significantly decreased rota-rod activity reflecting altered motor coordination. Pretreatment with VPA and NaB with Mn reversed the effects of Mn on the locomotor activity and motor coordination. VPA and NaB also attenuated the Mn-induced decrease in GLT-1 and GLAST mRNA and protein levels in the cerebral cortical and cerebellar regions of mice. These results suggest that VPA and NaB exert protective effects against Mn toxicity seem in vitro are also shown in vivo. VPA and NaB pretreatment in mice enhancing astrocytic glutamate transporter GLT-1 expression as well as locomotor activities. Future research endeavors are warranted to determine if the therapeutic potential of VPA and NaB is via common molecular mechanism, namely, inhibition of histone deacetylases.

Manganese-Enhanced Magnetic Resonance Imaging: Overview and Central Nervous System Applications With a Focus on Neurodegeneration

“…Other studies found little to no neurotoxicity in mice after single intraperitoneal (IP) doses of manganese chloride at 66 mg/kg (Fontaine et al, 2017), or short-term repeated IP injection in rats reaching final doses of 60 mg/kg (Galosi et al, 2017). To date, many studies have investigated alternative administration paradigms (see next section), alternative manganese-containing compounds (discussed in section “Mangafodipir”) and co-administration of additional compounds (Alahmari et al, 2015; Johnson et al, 2018) to mitigate any potential toxic effects of manganese in MEMRI and still retain useful imaging enhancement.…”

Valproate reduces neuroinflammation and neuronal death in a rat chronic constriction injury model

“…Its pharmacological effects involve diverse mechanisms that affect the transmission of nerve signals in vitro and in vivo . VPA is neuroprotective in some neurological diseases 2 , 3 . VPA was also found to decrease the excitation of neurons by N-methyl-D-aspartic acid (NMDA), inhibit voltage-gated sodium (Nav) channels, and modify the firing of neuronal cells 4 .…”

<i>N</i>-Linoleyltyrosine Protects against Transient Cerebral Ischemia in Gerbil <i>via</i> CB2 Receptor Involvement in PI3K/Akt Signaling Pathway

“…To better understand the effects of NITyr on global ischemia, both the cognitive and noncognitive behaviors of the gerbil were evaluated, for example locomotion, exploration, and anxiety-related behavior (OFT), motor function (RRT) and the ability of learning and memory (MWM). 17,18) NITyr had no effects on the autonomic activity, investigating behavior and anxiety behavior in the OFT, but increased the motor function in the RRT during the extension of the training time, indicating that NITyr could improve the motor function of the gerbil through enhancing the ability of learning and memory, but not affecting motor function. The improvement of learning and memory impairment might be related to the repairmen of damaged brain tissue rather than the improvement of motor ability of the gerbil.…”