Youssef Sari

Background: Relapse-like ethanol drinking behavior depends on changes in glutamate homeostasis in the mesocorticolimbic circuit. Extracellular glutamate regulation involves multiple transporters, mainly glutamate transporter 1 (GLT-1), which primarily removes the majority of extracellular glutamate; and cystine/glutamate antiporter (xCT) is co-localized with GLT-1 to be involved in this mechanism of maintaining glutamate homeostasis. Aims: Recent studies showed that MC-100093 treatment (i.p.), a β-lactam non-antibiotic known to increase GLT-1 and xCT expression, reduced chronic ethanol consumption in male and female alcohol-preferring (P) rats. This study examined whether MC-100093 may reduce relapse-like ethanol drinking behavior. Methods: P rats (both male and female) had access to 15% and 30% ethanol and water for 5 weeks and were treated with MC-100093 (100 mg/kg, i.p.) during the last 4 days of a 1-week deprivation period (week 6), continuing into 3 days of re-exposure (week 7). Results: MC-100093-treated rats exhibited lower ethanol intake and preference during re-exposure compared to saline-treated groups, across sexes. Additionally, MC-100093 treatment showed a sex difference in ethanol intake and preference after re-exposure. Moreover, MC-100093 attenuated ethanol-induced downregulation of GLT-1 and xCT expression in the medial prefrontal cortex (Prelimbic, PL; and Infralimbic, IL) and nucleus accumbens (core and shell) regions. Importantly, MC-100093 did not affect rat body weights. Conclusions: These results report for the first time the efficacy of GLT-1 modulator, MC-100093, on attenuating relapse-like ethanol drinking behaviors.

Background/Objective: Prolonged ethanol use can induce behavioral and physiological alterations and impair the liver’s capacity to metabolize ethanol, leading to hepatocyte injury. The spectrum of this disease ranges from fat accumulation to severe liver damage, including alcohol-related hepatitis and cirrhosis. MC-100093, a beta-lactam non-antibiotic compound, is known to modulate glutamate transporter-1 (GLT-1) and reduce ethanol drinking. Therefore, this study examined the effects of two optimal doses of MC-100093 on ethanol consumption and, consequently, ethanol-induced hepatic injury in both male and female alcohol-preferring (P) rats. Methods: Animals were divided into four groups and exposed to ethanol for six weeks. In week six, rats received intraperitoneal injections of saline, 100 mg/kg MC-100093, or 150 mg/kg MC-100093 for five consecutive days. Liver tissue samples were analyzed to assess GLT-1 and the cystine/glutamate antiporter (xCT), triglyceride levels, collagen type-1 (COL-1) deposition, and inflammatory cytokines. Results: MC-100093 effectively attenuated ethanol-induced liver damage by decreasing ethanol intake and restoring GLT-1, xCT, and COL-1 levels in the livers of both male and female P rats. Moreover, MC-100093 reversed ethanol-induced inflammation and reduced hepatic triglyceride levels. Conclusions: Our data show that MC-100093 effectively mitigates ethanol-induced liver injury.

Background: Amikacin is an effective aminoglycoside antibiotic, but its clinical use is limited by nephrotoxicity, hepatotoxicity, and neurotoxicity. N-acetylcysteine (NAC), a glutathione precursor and antioxidant, may help reduce these side effects. This study evaluated whether NAC attenuated selected amikacin-induced biochemical, inflammatory, and histopathological alterations in mice. Methods: Male Swiss albino mice were divided into four groups: control, amikacin, NAC, and amikacin-NAC, and the behavioral performance was assessed using the light-dark box test. Serum samples were collected for measurements of kidney and liver biomarkers, metabolic markers, and electrolytes (calcium, inorganic phosphate, and uric acid). A multiplex cytokine/chemokine panel was used to assess the effects of amikacin with/without NAC on systemic inflammation. Results: Amikacin-treated mice showed a reduction in the time spent in the light area, and this effect was improved by NAC. Amikacin also altered certain biochemistry parameters, increasing levels of aspartate transferase and albumin; these changes were attenuated by NAC. Amikacin caused marked increases in certain inflammatory cytokines and chemokines, including IL-6, IL-12p70, IL-22, IL-18, CXCL10, and CCL11. Treatment with NAC lowered IL-6, IL-12p70, IL-22, IL-18, CXCL10, and CCL11. The sparse partial least squares discriminant and heatmap analysis of the serum inflammatory profile revealed segregation of the amikacin group from the other three groups. Importantly, the histopathological assays on renal and cerebral cortex showed NAC caused improvements, with well-shaped tissues, attenuating the cortical histopathological alterations observed in animals treated with amikacin. Conclusions: These findings suggest that NAC may have the potential to attenuate certain biochemical, inflammatory, and histopathological alterations associated with high-dose amikacin exposure.

Rationale Tobacco companies reported that electronic cigarette products were developed to reduce the adverse health effects of conventional cigarettes; however, impairments of lung, brain, and kidney are reported in subjects exposed to electronic cigarettes. Both types contain nicotine in varying amounts, raising concerns about nicotine’s toxicity in the body. Studies suggest that modulating glutamate transporters with beta-lactam, ceftriaxone, can reduce nicotine intake. Objectives We here tested the pharmacological effects of ceftriaxone and MC-100093 as a novel synthetic beta-lactam, which doesn’t have antibiotic action, in mouse model of nicotine self-administration. Methods Male C57BL/6 mice were exposed to nicotine-self administration for five weeks, and the effects of ceftriaxone and MC-100,093 on nicotine intake were determined in week 5. Brains were collected for determination of changes in glutamatergic system and neuroinflammatory cytokines levels. Blinded in silico study was conducted to determine the binding properties of ceftriaxone and MC-100093 to glutamate transporter 1 (GLT-1). Results The results revealed that MC-100093 and ceftriaxone reduced nicotine self-administration. Both compounds attenuated nicotine-induced downregulation of glutamate transporters such as GLT-1 and cystine/glutamate antiporter (xCT), and this effect was associated with attenuation of nicotine-induced increase in glutamate content in the nucleus accumbens. Furthermore, MC-100093 and ceftriaxone attenuated nicotine-increased in TNF-α and IL-6, which indicate that both compounds have a neuroprotective effect. Additionally, the in-silico docking study predicted that both MC-100093 and ceftriaxone exhibited acceptable binding properties into GLT-1. Conclusion Together, these data report potential therapeutic effects of MC-100093 targeting glutamate transporters for treating substance use disorders, particularly tobacco-use disorder.

Background: Ethanol consumption disrupts glutamate homeostasis in several brain regions. The uptake of extracellular glutamate is regulated in the majority by the astrocytic glutamate transporter 1 (GLT-1), and cystine-glutamate exchanger (xCT) contributes to this regulatory effect. Chronic ethanol consumption is well known to downregulate GLT-1 expression in several reward brain regions, including the nucleus accumbens (NAc). Objectives: Recently, we reported that a novel beta-lactam, MC-100093, attenuated ethanol consumption and normalized the expression of GLT-1 in the subregions of the NAc. Based on these findings, we aimed in this study to determine the dose-dependent effect of MC-100093 in attenuating ethanol consumption and whether this attenuating effect is associated with restoration of glutamate uptake. In addition, we focused on whether the effects of MC-100093 on GLT-1 are mediated through the mammalian target of rapamycin (mTOR), protein kinase B (Akt), and nuclear factor-kappa B (NF-κB) signaling pathways. Methods: Male and female alcohol-preferring (P) rats are grouped into 4 groups. Other than control groups all the 3 groups had free access to ethanol (15% and 30% v/v), and water for 5 weeks. On week 6, rats received intraperitoneal injection (i.p.) of MC-100093 at a dosage of 100 or 150 mg/kg, or saline, for 5 days. The Na+ dependent and Na+ independent glutamate uptake is measured by radioactive glutamate uptake assay. The expression of GLT-1, xCT, mTOR, phospho-Akt (p-Akt), kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IkBa), and NF-κB are determined by Western blot analysis. Results: MC-100093 treatment reduced ethanol drinking in male and female P rats. MC-100093 was associated with an increase in Na+-dependent and Na+-independent glutamate uptake. Furthermore, MC-100093 treatment attenuated ethanol-induced decrease in GLT-1, xCT, NF-κB, and p-Akt expression in the NAc. Conclusions: These findings demonstrate that MC-100093 attenuated ethanol consumption and regulated glutamate uptake through normalizing GLT-1 expression.

Background/Objectives: Neuropathic pain is challenging to treat, often resistant to current therapies, and associated with significant side effects. Pregabalin, an anticonvulsant that modulates calcium channels, is effective but can impair mental and motor functions, especially in older patients. To improve patient outcomes, reducing the doses of pregabalin and combining it with other drugs targeting different neuropathic pain mechanisms may be beneficial. TNF-α blockers such as etanercept have shown potential in addressing neuropathic pain by affecting sodium channels, synaptic transmission, and neuroinflammation. This study evaluates the efficacy and safety of combining low doses of etanercept and pregabalin in allodynia and nociceptive tests. Materials and Methods: Male C57/BL6 mice underwent chronic constriction injury (CCI) of the sciatic nerve to induce neuropathic pain. They were divided into seven groups: sham control, CCI control, low and high doses of pregabalin, low and high doses of etanercept, and a combination of low doses of both drugs. Behavioral tests, including von Frey, hot-plate, and rotarod tests, were used to assess pain responses and motor activity. Results: The results indicated that a high dose of pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia but impaired motor function. Conversely, low doses of etanercept alone had no significant effect. However, the combination of low doses of etanercept (20 mg/kg) and pregabalin (5 mg/kg) effectively alleviated pain without compromising locomotor activity. Conclusions: These results suggest a novel therapeutic strategy for neuropathic pain, enhancing analgesic efficacy while minimizing adverse effects.