Edaravone mitigates cognitive impairment and hippocampal injury in juvenile rats with obstructive sleep apnea hypopnea syndrome via regulation of cAMP/PKACREB pathway

Purpose: To investigate the influence of edaravone on cognitive impairment and hippocampal injury in juvenile rats with obstructive sleep apnea hypopnea syndrome (OSAHS), and the mechanism involved.Methods: Fifty-four young Wistar rats were randomly selected into control, intermittent hypoxia and edaravone groups. The contents of the antioxidants CAT, Mn-SOD, Cu/Zn SOD and oxidative stress products malondialdehyde (MDA) in hippocampus were assayed and compared. The expressions of brain-derived neurotrophic factor (BDNF), Bcl-2, CREB, p-CREB and PKAc were determined.Results: The times taken to cross the target quadrant and the platform; levels of CAT and Mn-SOD, as well as protein levels of BNDF, Bcl-2, p-CREB and PKAc were markedly lower in intermittent hypoxia group than in controls; and MDA contents, 8-OHdG and protein hydroxyl were markedly higher in intermittent hypoxic rats group than in controls. Time taken to cross the platform and quadrant; activities of CAT and Mn-SOD, and protein concentrations of BDNF, Bcl-2, p-CREB and PKAc were markedly higher in the edaravone-treated rats than in intermittent hypoxia rats.Conclusion: Edaravone significantly mitigated cognitive damage and hippocampal lesions in OSAHS rats via a mechanism related to alleviation of oxidative stress and up-regulation of the expressions of p-CREB and its downstream proteins BDNF and Bcl-2. This finding provides a theoretical basis for research and development of new drugs against OSAHS.

Heavy Ion Minibeam Therapy: Side Effects in Normal Brain

The purpose of this work was to investigate whether minibeam therapy with heavy ions might offer improvements of the therapeutic ratio for the treatment of human brain cancers. To assess neurotoxicity, we irradiated normal juvenile rats using 120 MeV lithium-7 ions at an absorbed integral dose of 20 Gy. Beams were configured either as a solid parallel circular beam or as an array of planar parallel minibeams having 300-micron width and 1-mm center-to-center spacing within a circular array. We followed animals for 6 months after treatment and utilized behavioral testing and immunohistochemical studies to investigate the resulting cognitive impairment and chronic pathologic changes. We found both solid-beam therapy and minibeam therapy to result in cognitive impairment compared with sham controls, with no apparent reduction in neurotoxicity using heavy ion minibeams instead of solid beams under the conditions of this study.

Reversing anterior insular cortex neuronal hypoexcitability attenuates compulsive behavior in juvenile rats

Development of self-regulatory competencies during adolescence is partially dependent on normative brain maturation. Here we report that juvenile rats as compared to adults exhibit impulsive and compulsive-like behavioral traits, the latter being associated with lower expression of mRNA levels of the immediate early gene zif268 in the anterior insula (AI). This observation suggests that deficits in AI function in juvenile rats could explain their immature pattern of interoceptive cue integration in rational decision-making and compulsive phenotype. In support of this, here we report hypoexcitability of juvenile layer-V pyramidal neurons in the AI, concomitant with reduced glutamatergic synaptic input to these cells. Chemogenetic activation of the AI attenuated the compulsive trait suggesting that delayed maturation of the AI results in suboptimal integration of sensory and cognitive information in adolescents and this contributes to inflexible behaviors in specific conditions of reward availability.

Txn1 mutation causes epilepsy associated with vacuolar degeneration in the midbrain

Thioredoxin (TXN), encoded by Txn1, acts as a critical antioxidant in the defense against oxidative stress by regulating the dithiol/disulfide balance of interacting proteins. The role of TXN in the central nervous system (CNS) is largely unknown. A phenotype-driven study of N-ethyl-N-nitrosourea-mutated rats with running seizures at around five-week of age revealed the relevance of Txn1 mutations to CNS disorders. Genetic mapping identified Txn1-F54L in epileptic rats. The insulin-reducing activity of Txn1-F54L rats was approximately one-third that of the wild-type. Vacuolar degeneration in the midbrain, mainly in the thalamus and the inferior colliculus, was observed in the Txn1-F54L rats. The lesions displayed neuronal and oligodendrocyte cell death. Neurons in Txn1-F54L rats showed morphological changes in the mitochondria. Vacuolar degeneration began at three weeks of age, and spontaneous repair began at seven weeks; a dramatic change from cell death to repair occurred in the midbrain during a restricted period. In conclusion, Txn1 is essential for the development of the midbrain in juvenile rats.