Search

Many studies have shown that cytochrome P450 (CYP) gene polymorphisms are usually associated with an increased risk of cardiovascular and cerebrovascular diseases. To explore the association of CYP2C8 and CYP2J2 gene polymorphisms with hypertensive intracerebral hemorrhage (HICH) in the Han Chinese population.Forty HICH patients and 40 control subjects were recruited for this study. Two single nucleotide polymorphisms (SNP) (rs1058932, rs2275622) in the CYP2C8 gene and two SNPs (rs2271800, rs1155002) in the CYP2J2 gene were selected for genotyping by direct sequencing. Statistical analysis was applied to examine the effect of genetic variation on HICH.We found that variant alleles of CYP2C8 rs1058932 (A) and rs2275622 (C) were both significantly associated with HICH, especially in females. We also found significant associations of CYP2C8 rs1058932 (A) and rs2275622 (C) variant alleles with poor outcomes in HICH patients, especially in males.CYP2C8 gene polymorphisms might increase the risk of HICH in the Han Chinese population and might lead to poor outcomes. This finding adds to the body of literature supporting novel therapeutic strategies for HICH.

Intracerebral hemorrhage (ICH) is a common and severe cerebrovascular disease that has high mortality. Few survivors achieve self-care. Currently, patients receive only symptomatic treatment for ICH and benefit poorly from this regimen. Inflammatory cytokines are important participants in secondary injury after ICH. Increases in proinflammatory cytokines may aggravate the tissue injury, whereas increases in anti-inflammatory cytokines might be protective in the ICH brain. Inflammatory cytokines have been studied as therapeutic targets in a variety of acute and chronic brain diseases; however, studies on ICH are limited. This review summarizes the roles and functions of various pro- and anti-inflammatory cytokines in secondary brain injury after ICH and discusses pathogenic mechanisms and emerging therapeutic strategies and directions for treatment of ICH.

Threohydroxyaspartate (THA) causes glutamate excitotoxicity in motor neurons in organotypic culture of rat spinal cord. Some drugs, including sulforaphane (SF) and riluzole, can protect motor neuron against excitotoxicity. It has been demonstrated that SF is a potent inducer of Phase II enzymes, while riluzole is a classic anti-glutamate agent. The objective of the current study is to investigate whether the combination of SF and riluzole is superior to either one used alone. In our study, the combination of SF with riluzole not only stimulates the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), reduced nicotinamide adenine dinucleotide phosphate (NADPH): quinone oxidoreductase 1 (NQO1) and heme oxygenase 1 (HO-1), but also reduces the extracellular accumulation of glutamate. When used at optimal doses, SF (10 microM) and riluzole (5 microM), either alone or in combination, all exert significant and similar neuroprotection, as measured by the number of motor neuron, medium malondialdehyde (MDA) level and lactate dehydrogenase (LDH) level. When used at low doses, the combination is better than each agent used alone. In conclusion, these results suggest the potential utility of combination use of SF and riluzole for protection of motor neuron against excitotoxicity.

Threohydroxyaspartate (THA)-induced glutamate excitotoxicity in organotypic culture of rat spinal cord is a well-known model of motor neuron degeneration. THA causes accumulation of synaptic glutamate and over stimulation of the postsynaptic receptor by inhibiting glutamate uptake. This model has also been used to identify agents that inhibit glutamate excitotoxicity by increasing the expression of glutamate transporter. We now show that THA also increases iron level in rat spinal cord tissue, with concomitant modulation of key iron transport and storage proteins, including transferrin receptor, divalent metal-ion transporter 1 and ferritin. More significantly, iron chelator deferoxamine (DFO) was able to completely prevent THA-induced motor neuron degeneration. The protective effect of DFO did not involve enhancing glutamate uptake. These data provide new mechanistic insight into THA-induced glutamate excitotoxicity and suggest that blocking THA-induced iron rise alone may be sufficient for prevention of glutamate excitotoxicity.

Epigallocatechin-3-gallate (EGCG) is a major component of green tea polyphenols which displays potential properties of anticancer and neuroprotection. Here we show that protection of motor neuron by EGCG is associated with regulating glutamate level in organotypic culture of rat spinal cord. In this model, EGCG blocked glutamate excitotoxicity caused by threohydroxyaspartate, an inhibitor of glutamate transporter. This property of EGCG may be not due to its intrinsic antioxidative activity, because another antioxidant could not regulate glutamate level under the same condition. These results show that EGCG may be a potential therapeutic candidate for neurodegenerative diseases involving glutamate excitotoxicity such as ALS.