Paola Ballesteros-Zebadúa

Radiation-Induced Neuroinflammation and Radiation Somnolence Syndrome

Cranial irradiation remains a standard treatment for malignant and benign brain diseases. Although this procedure helps to lengthen the life expectancy of the patient, the appearance of adverse effects related to radiation-induced injury is inevitable. Radiation somnolence syndrome (RSS) has been described as a delayed effect observed mainly after whole-brain radiotherapy in children. The RSS was first linked to demyelination, but more recently it has been proposed that the inflammatory response plays a primary role in the aforementioned syndrome. To evaluate the feasibility of this hypothesis, we explored previous work about RSS and reviewed published research that included measurements of the inflammatory response in models of brain exposure to ionizing radiation. Pro-inflammatory cytokines such as interleukin-1β, tumor necrosis factor-α, interleukin-6 and interleukin-18 as well as other inflammatory markers such as cyclooxygenase-2, prostaglandin E₂, glial fibrillary acid protein, intercellular adhesion molecule-1 and nuclear factor-κB appear to be involved in the brains response to radiation. However, certain publications have described the somnogenic effects of these cytokines and inflammatory markers. Although the radiation response is a complex phenomenon that involves several molecular and cellular processes, we propose that inflammation may be closely related to the adverse effects of brain irradiation and therefore to the etiology of RSS.

Sleep deprivation and sleep recovery modifies connexin36 and connexin43 protein levels in rat brain.

Gap junctional communication is mainly mediated by connexin36 and connexin43 in neurons and astrocytes, respectively. It has been suggested that connexin36 allows electrical coupling between neurons whereas connexin43 participates in several process including release of ATP. It was recently reported that blockage of gap junctional communication mediated by connexin36 can disrupt the sleep architecture of the rat. However, there is no experimental approach about effects of sleep deprivation on connexins expression. Therefore, we examined in adult male Wistar rats whether protein levels of connexin36 and connexin43 change in pons, hypothalamus, and frontal cortex after 24 h of total sleep deprivation and 4 h of sleep recovery. Western blot revealed that total sleep deprivation significantly decreases the levels of connexin36 in the hypothalamus and this decrease maintains after sleep recovery. Meanwhile, connexin43 is not altered by total sleep deprivation but interestingly the sleep recovery period induces an increase of this connexin. These results suggest that electrical coupling between hypothalamic neurons could be altered by sleep deprivation and that sleep recovery drives changes in connexin43 expression probably as a mechanism related to ATP release and energy regulation during sleep.

Differences in HIV-1 Viral Loads Between Male and Female Antiretroviral-untreated Mexican Patients

BACKGROUND AND AIMS HIV-1 viral load is used to monitor AIDS progression and effect of antiretroviral therapy (ART). Several reports have indicated that the HIV-1 viral load of infected individuals is lower in females than in males. There are no reports exploring this issue in the Mexican population. We analyzed the relationship between sex and viral load in Mexican patients differing in CD4 T-cell count, age and treatment status. METHODS A retrospective study was performed in 3949 male and 696 female HIV-1-infected individuals. Statistical distributions were compared using the Mann-Whitney U nonparametric test. RESULTS Among the antiretroviral-untreated group, females had a significantly lower viral load than males (0.52 female/male median viral load ratio, p = 0.008). When classified according to different ranges of CD4⁺ T cell counts, females had consistently lower viral loads than males, although statistical significance was achieved only for the group in the range of 201-350 (p = 0.014). Patients with the lowest CD4⁺ T-cell counts showed similar viral loads for both sexes. No differences were observed in the ART group. CONCLUSIONS This study demonstrates a baseline difference in viral load between male and female ART-untreated Mexican patients. The overall tendency indicating a lower viral load in females in the same ranges of CD4⁺ T-cell counts than males, suggests that the lower viral load in females is not indicative of a lower risk of developing AIDS. These observations suggest a significant influence of sex on viral dynamics and immune response despite variations in demographic factors.

Unilateral microinjection of carbenoxolone into the pontis caudalis nucleus inhibits the pentylenetetrazole-induced epileptiform activity in rats

Pontine reticular formation (PRF) is involved in the generation and maintenance of generalized epileptic seizures. Carbenoxolone (CBX) is a gap junction blocker with anticonvulsant properties. Therefore, the present study was designed to explore the effects of CBX microinjected into the pontis caudalis nucleus (PnC) on generalized tonic-clonic seizures (GTCS) and epileptiform activity induced by pentylenetetrazole (PTZ). All control rats presented GTCS after a single dose of PTZ. The microinjection of CBX into the PnC reduced the GTCS incidence induced by PTZ. Moreover, the CBX significantly increased the latency to the first myoclonic jerk. Additionally, CBX significantly decreased the spectral power and the amplitude of the epileptiform activity induced by PTZ. By contrast, the microinjection of a gap junction opener (trimethylamine) did not cause anticonvulsant effects and even increased the duration of the GTCS. These findings suggest that the PnC is a particular nucleus where the CBX could exert its action mechanisms and elicit anticonvulsant effects.

Whole-brain irradiation increases NREM sleep and hypothalamic expression of IL-1β in rats

Abstract Purpose: Although it has mainly been described qualitatively, whole brain irradiation induces somnolence in patients with malignant diseases. Therefore, we used a rat model to quantify the effects of irradiation of healthy brain tissue on both sleep-wake patterns and the expression of the pro-inflammatory cytokine interleukin-1β (IL-1β), which is known to induce sleep. Materials and methods: Different groups were examined at three time points after irradiation (1 day, 30 days and 60 days). Polysomnographic recordings were performed on each rat before and after total cranial irradiation (12 Gy). IL-1β protein levels in several brain regions were assessed by enzyme-linked immunosorbent assays, and site-specific immunoreactivity was observed by immunofluorescence. Results: We found that both non-rapid eye movement sleep and IL-1β protein expression in the hypothalamus increased 30 days after irradiation. Conclusions: Whole brain irradiation increases sleep in our rat model, and this finding is similar to qualitative reports from patients. Because IL-1β has been proposed as a sleep-promoting molecule, we propose that the polysomnographic results may be attributable, at least in part, to the delayed overexpression of IL-1β in the hypothalamus.

Quinine and carbenoxolone enhance the anticonvulsant activity of some classical antiepileptic drugs

Abstract Objective Quinine (QUIN) and carbenoxolone (CNX) elicit anticonvulsant effects typically characterized by the reduction of the epileptiform activity as well as changes in behavioral parameters related to seizures. Therefore, the aim of this study was to analyze the effects of these molecules on the anticonvulsant activity of some classical antiepileptic drugs. Methods Male Wistar rats were used. Valproate (VPA), phenytoin (PHT), or carbamazepine (CBZ) was administered at sub-therapeutic doses for intraperitoneal via. Subsequently, animals were administered with a single dose of QUIN or CNX. The anticonvulsant activity was evaluated with the maximal electroshock (MES) test and pentylenetetrazole (PTZ) administration. Additionally, the plasma levels of CBZ were determined using an HPLC method. Results All the control rats presented generalized tonic–clonic seizures after the MES test or the administration of PTZ. For the MES test, all of the antiepileptic drugs increased their anticonvulsant activity when were co-administered with QUIN. For the PTZ test, only the combination CBZ plus QUIN significantly increased the percentage of protection against the generalized tonic–clonic seizures. The co-administration of CBZ plus QUIN resulted in an augmented concentration of CBZ in plasma. Discussion The present study shows that QUIN and CNX enhance the anticonvulsant activity of some classical antiepileptic drugs. However, only the combination CBZ/QUIN had significant effects on both MES and PTZ models. Such anticonvulsant activity could be attributed to increased levels of CBZ in plasma. We propose that these molecules could improve the pharmacological actions of antiepileptic drugs administered at sub-therapeutic doses.