Treatment with AAV1-Rheb(S16H) provides neuroprotection in a mouse model of photothrombosis-induced ischemic stroke.

We recently reported that upregulation of the constitutively active ras homolog enriched in brain [Rheb(S16H)], which induces the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, can protect adult neurons, mediated by the induction of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), in animal models of neurodegenerative diseases. Here we show that neuronal transduction of Rheb(S16H) using adeno-associated virus serotype 1 provides neuroprotection in a mouse model of photothrombosis-induced ischemic stroke. Rheb(S16H)-expressing neurons exhibited neurotrophic effects, such as mTORC1 activation, increases in neuronal size, and BDNF production, in mouse cerebral cortex. Moreover, the upregulation of neuronal Rheb(S16H) significantly attenuated ischemic damage and behavioral impairments as compared to untreated mice, suggesting that Rheb(S16H) upregulation in cortical neurons may be a useful strategy to treat ischemic stroke.

Perspective: Therapeutic Potential of Flavonoids as Alternative Medicines in Epilepsy.

Epilepsy is a chronic neurological disorder that affects many people worldwide. Temporal lobe epilepsy is the most common and most studied type of epilepsy, but the pathological mechanisms underlying this condition are poorly understood. More than 20 antiepileptic drugs (AEDs) have been developed and used for the treatment of epilepsy; however, 30% of patients still experience uncontrolled epilepsy and associated comorbidities, which impair their quality of life. In addition, various side effects have been reported for AEDs, such as drowsiness, unsteadiness, dizziness, blurred or double vision, tremor (shakiness), greater risk of infections, bruising, and bleeding. Thus, critical medical needs remain unmet for patients with uncontrolled epilepsy. Flavonoids belong to a subclass of polyphenols that are widely present in fruits, vegetables, and certain beverages. Recently, many studies have reported that some flavonoids elicit various beneficial effects in patients with epilepsy without causing the side effects associated with conventional medical therapies. Moreover, flavonoids may have a property of regulating microRNA expression associated with inflammation and cell survival. These findings suggest that flavonoids, which are more effective but impose fewer adverse effects than conventional AEDs, could be used in the treatment of epilepsy.

Beneficial Effects of Hesperetin in a Mouse Model of Temporal Lobe Epilepsy.

Abnormal reorganization of the dentate gyrus and neuroinflammation in the hippocampus represent characteristic phenotypes of patients suffering from temporal lobe epilepsy. Hesperetin, a flavanone abundant in citrus fruit, is known to have protective effects by preventing inflammation and oxidative stress in neuronal cultures and in the adult murine brain. However, the protective effects of hesperetin against epileptic seizures in vivo remain unclear, despite one study reporting anticonvulsant effects in vitro. In this study, we report that oral administration of hesperetin not only delays the onset of seizures triggered by kainic acid (KA) but also contributes to the attenuation of granule cell dispersion in the KA-treated hippocampus. Moreover, we observed that hesperetin administration inhibited the expression of pro-inflammatory molecules produced by activated microglia in the hippocampus. Thus, administration of hesperetin might be beneficial for preventing epileptic seizures.

Nobiletin protects dopaminergic neurons in the 1-methyl-4-phenylpyridinium-treated rat model of Parkinson's disease.

This study investigated the effect of nobiletin, a flavonoid found in citrus fruits, on the degeneration of dopaminergic (DA) neurons in a neurotoxin model of Parkinson's disease (PD). 1-Methyl-4-phenylpyridinium (MPP(+)) was unilaterally injected into the median forebrain bundle of rat brains (to generate a neurotoxin model of PD) with or without daily intraperitoneal injection of nobiletin. Our results showed that nobiletin treatment at 10 mg/kg bw, but not at 1 or 20 mg/kg bw, significantly protected DA neurons in the substantia nigra (SN) of MPP(+)-treated rats. In parallel to the neuroprotection, nobiletin treatment at 10 mg/kg inhibited microglial activation and preserved the expression of the glial cell line-derived neurotrophic factor, which is a therapeutic agent against PD, in the SN. These results suggest that the proper supplementation with nobiletin may protect against the neurodegeneration involved in PD.

Silibinin attenuates MPP⁺-induced neurotoxicity in the substantia nigra in vivo.

Parkinson's disease (PD) is characterized by degeneration of the nigrostriatal dopaminergic (DA) pathway. The cause of neuronal death in PD is largely unknown, but it is becoming clear that inflammation plays a significant role in the pathophysiology of PD. Silibinin is a major flavonoid in milk thistle which has an anti-inflammatory activity. We investigated whether silibinin could have neuroprotective effects on DA neurons in the 1-methyl-4-phenylpyridinium ion (MPP(+))-treated animal model of PD in vivo. To address this question, animals received intraperitoneal (i.p.) injections 10, 50, or 100 mg/kg of silibinin, starting 1 day before MPP(+) injection and continued daily until 6 days post-lesion for tyrosine hydroxylase (TH) staining, or until 1 hour prior to the MPP(+) injection to examine the expression levels of inflammatory proteins. Finally, their brains were harvested at the indicated time points for the analyses. Silibinin treatment with 10 mg/kg had no significantly neuroprotective effects in the substantia nigra (SN). However, 50 and 100 mg/kg of silibinin ameliorated the MPP(+)-induced neurotoxicity in the SN in a dose-dependent manner, and the increased levels of inflammatory molecules such as tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß) and inducible nitric oxide synthase (iNOS) by MPP(+) treatment were attenuated by treatment with 100 mg/kg of silibinin. These results indicate that silibinin could be a useful and beneficial natural product offering promise for the prevention of DA neuronal degeneration involved in PD.