Histamine Receptor intervention for ALS patients begins well after disease onset, and because of the array of cell autonomous and nonautonomous dysfunctions at this point, it is unlikely that one drug will affect enough pathways to produce lasting results. Drug combinations that include riluzole but affect additional pathways may therefore provide greater protection. Conclusion. Prolonged riluzole treatment had minimal effects on motoneuron firing behavior and remained a potent inhibitor of the PIC and repetitive firing when reapplied. It therefore seems possible that riluzole continues to decrease motoneuron excitability but its therapeutic effects are eventually overwhelmed by other pathologies associated with ALS. Manganese is an essential nutrient, which is functioning as a critical cofactor for many enzymes in many biochemical and cellular reactions in the animal bodies. However, occupational or environmental exposure to excessive Mn would cause manganism which is resembled smad signaling pathway Parkinson disease. Besides, with the increasing usage of methylcyclopenta dienyl manganese tricarbonyl, an antiknock agent in gasoline, the health risks of Mn exposure are rising severely.
After uptake into the bodies of mammals, Mn can go through the blood brain PARP barrier by DMT 1 mediated and/or transferrin mediated pathway and accumulate in striatum and globus pallidus. Based on the previous studies, it was found that the levels of Mn could reach to 100500 M in brain at pathological conditions. To date, the mechanisms of manganism were still unknown. In central nervous system, astrocytes not only can produce trophic activities for neurons but also can accumulate a large number of Mn in it. Therefore, it is reasonable to presume that toxic effects on astrocytes may play a key role on the occurrence of Mn neurotoxicity. The cell cycle entails a series of macromolecular events that lead to cell replication. It has been documented that cell cycle disruption involved in the transduction of cell death signals. Apoptosis is a physiological cell death. It had been found to be caused by Mn exposure in rat pheochromocytoma zoledronate cells, neural stem cells, and HeLa cells. However, it is not known whether cell cycle aberrations and apoptosis are involved in Mn toxicity on astrocytes. Riluzole, a glutamatergic modulator, is the only drug that approved for amyotrophic lateral sclerosis treatment. It had also acted protective effects on animal models of Huntington’s disease, Parkinson’s disease, and brain ischemia.
In vitro, some studies found that riluzole was a protective agent to reverse Glu toxicity to astrocytes. This might be because of its effects on enhancing Glu uptake and increasing the affinity of Glu to GluTs. It had been documented that dysfunction of astrocytes on glutamate transport is believed to be associated with manganism. This excessive Glu accumulation would lead to toxic effects on astrocytes. However, data regarding riluzole possible effects on antagonizing cytotoxicity, cell neuron cycle aberrations, and apoptosis on astrocytes after Mn exposure are still few. In the present study, we investigated the effects of MnCl2 exposure on cell viability, lactate dehydrogenase leakage, morphological changes, cell cycle progression, and apoptosis in the cultured astrocytes after Mn exposure.