Methamphetamine (MA) is one of the most commonly abused drugs in the world by illegal drug users. Addiction to MA is a serious public health problem and effective therapies do not exist to date. It has also been reported that behavior induced by psychostimulants such as MA is related to histone deacetylase (HDAC). MeBib is an HDAC6 inhibitor derived from a benzimidazole scaffold. Many benzimidazole-containing compounds exhibit a wide range of pharmacological activity. In this study, we investigated whether HDAC6 inhibitor MeBib modulates the behavioral response in MA self-administered rats. Our results demonstrated that the number of active lever presses in MA self-administered rats was reduced by pretreatment with MeBib. In the hippocampus of rats, we also found MA administration promotes GluN2B, an NMDA receptor subunit, expression, which results in sequential activation of ERK/CREB/BDNF pathway, however, MeBib abrogated it. Collectively, we suggest that MeBib prevents the MA seeking response induced by MA administration and therefore, represents a potent candidate as an MA addiction inhibitor.

Methamphetamine (METH) acts strongly on the nervous system and damages neurons and is known to cause neurodegenerative diseases such as Alzheimer's and Parkinson's. Flavonoids, polyphenolic compounds present in green tea, red wine and several fruits exhibit antioxidant properties that protect neurons from oxidative damage and promote neuronal survival. Especially, epicatechin (EC) is a powerful flavonoid with antibacterial, antiviral, antitumor and antimutagenic effects as well as antioxidant effects. We therefore investigated whether EC could prevent METH-induced neurotoxicity using HT22 hippocampal neuronal cells. EC reduced METH-induced cell death of HT22 cells. In addition, we observed that EC abrogated the activation of ERK, p38 and inhibited the expression of CHOP and DR4. EC also reduced METH-induced ROS accumulation and MMP. These results suggest that EC may protect HT22 hippocampal neurons against METH-induced cell death by reducing ER stress and mitochondrial damage.

Purpose: The luminal subtype of breast cancer has heterogeneous biological characteristics with respect to the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor-2 (HER2), and Ki-67. We analyzed luminal B breast cancer subcategorized by PR expression and identified clinically relevant prognostic factors. Methods: We collected the clinical and pathologic data of 247 breast cancer patients (stage 1-4) who were diagnosed with luminal B subtype, defined as ER- and/or PR-positive and/or HER2-positive and with a high Ki-67 proliferation index (>14%). We classified them into PR intact and PR low groups according to PR expression pattern. We also analyzed the clinical and pathological data of each group, including age at diagnosis, tumor size, node metastasis, breast and axillary operative method, margin involvement, tumor-node-metastasis (TNM) stage, histological grade, nuclear grade, number of tumors, and expression of ER, PR, Ki-67, and Bcl-2; evaluated recurrence or metastatic characteristics; and analyzed disease-free survival (DFS) and overall survival (OS) in both groups. Results: Among the 247 luminal B breast cancer patients (stage 1-4), 141 were classified into the PR intact group (57.1%) and 106 into the PR low group (42.9%). The PR low group was associated with age >50 years (p=0.001), low Bcl-2 expression (p<0.001), and high proportion of mastectomies (p<0.001). DFS and OS were significantly lower in the PR low group (p=0.025 and 0.024, respectively). Conclusion This study showed that decreased in PR expression (PR low group) in luminal B breast cancer was related to poor prognosis compared to normal PR expression (PR intact group).