Levetiracetam attenuates diabetes-associated cognitive impairment and microglia polarization by suppressing neuroinflammation.

Introduction: Cognitive impairment is a common complication and comorbidity of diabetes. However, the underlying mechanisms of diabetes-associated cognitive dysfunction are currently unclear. M1 microglia secretes pro-inflammatory factors and can be marked by CD16, iNOS, Iba1 and TNF-ɑ. The decline of M2 microglia in the diabetic rats indicates that high glucose promotes the differentiation of microglia into the M1 type to trigger neuroinflammatory responses. Moreover, there is a lack of strong evidence for treatments of diabetes-associated cognitive impairment in addition to controlling blood glucose. Methods: Diabetic rats were established by intraperitoneal injection of one dose of streptozotocin (60 mg/kg). Polarization transitions of microglia were induced by high glucose treatment in BV2 cells. Levetiracetam was orally administered to rats 72 h after streptozotocin injection for 12 weeks. Results: In STZ-induced diabetic rats, the results demonstrated that levetiracetam improved rat cognitive function (Morris water maze test) and hippocampus morphology (Hematoxylin-eosin staining), and the effect was more evident in the high-dose levetiracetam group. Microglia activation in the hippocampus was inhibited by levetiracetam treatment for 12 weeks. Serum levels of TNF-α, IL-1ß, and IL-6 were reduced in the LEV-L and LEV-H groups, and IL-1ß level was obviously reduced in the LEV-H group. In vitro, we found that levetiracetam 50 µM attenuated high-glucose induced microglial polarization by increasing IL-10 level and decreasing IL-1ß and TNF-α levels. Moreover, levetiracetam 50 µM increased and decreased the proportion of CD206+/Iba1+ and iNOS+/Iba1+cells, respectively. Western blot analysis illustrated that LEV 50 µM downregulated the expression of MyD88 and TRAF6, and phosphorylation of TAK1, JNK, p38, and NF-κB p65. The effect of levetiracetam on the anti-polarization and expression of p-JNK and p-NF-κB p65 were partly reversed by anisomycin (p38 and JNK activators). Discussion: Together, our data suggest that levetiracetam attenuates streptozotocin-induced cognitive impairment by suppressing microglia activation. The in vitro findings also indicate that the levetiracetam inhibited the polarization of microglia via the JNK/MAPK/NF-κB signaling pathway.

[Diagnosis and treatment of pulmonary hypertension caused by sleep hypoventilation: analysis of 4 cases in a family].

OBJECTIVE: To summarize the experience in diagnosis and treatment of pulmonary hypertension caused by sleep hypoventilation. METHODS: The clinical data of 4 patients in a family with pulmonary hypertension caused by sleep hypoventilation, full brothers and sisters, 2 (Cases 1 and 2) being treated presently and 2 (Cases 3 and 4) being deceased and traced by family medical history, were retrospectively analyzed. RESULTS: Three of the 4 cases (cases 1, 3, and 4) were misdiagnosed as with cor pulmonale combined with pulmonary hypertension, and one case (case 2) was misdiagnosed as with primary pulmonary hypertension. Polysomnography (PSG) revealed alveolar hypoventilation-induced long period of oxygen desaturation at sleep in Cases 1 and 2, thus confirming the diagnosis. Pulmonary function test showed that the percentage of maximum inspiratory pressure (PImax) in predicted value (51.5% and 20.9%) and the maximum expiratory pressure (PEmax) in predicted value (51.3% and 29.6%) decreased, the percentage of mouth occlusion pressure (P0.1) in predicted value (141% and 133%) compensatively increased, and the respiratory muscle strength decreased in Cases 1 and 2, which suggested that there was neuromuscular disorder in these patients. Treated by noninvasive ventilation the symptoms of these 2 patients were improved and they were discharge at last. Subsequently, they were treated by long-term night noninvasive ventilation at home, and returned to normal work and life. During the follow-up for 22 and 12 months respectively after discharge, PSG showed that the alveolar hypoventilation-induced long period oxygen desaturation at sleep had been greatly improved, and echocardiogram showed that the pulmonary pressure was greatly decreased. CONCLUSION: For the patients with unexplained pulmonary hypertension, PSG monitoring and pulmonary function tests such as PImax, PEmax, and P0.1 help determine the etiology, and long-term night noninvasive ventilation at home can improve the outcome of sleep hypoventilation-induced pulmonary hypertension.

[Respiration control dysfunction and the relationship to sleep-disordered breathing in patients with chronic obstructive pulmonary disease].

OBJECTIVE: To analyze the polysomnographic (PSG) features of sleep apnea hypopnea syndrome (SAHS) in patients with chronic obstructive pulmonary disease (COPD), and to define the association between SAHS and respiratory control disorder. METHODS: Three hundred patients with stable COPD were screened for SAHS using questionnaire, Epworth sleep scale (ESS) and home pulse oximeter testing. Those with ESS > or = 10 or oxygen desaturation over 3% more than 5 times per hour sleep were under further PSG testing. The PSG features were compared between COPD patients with apnea hypopnea index (AHI) > 10 and 118 SAHS patients with normal lung function. The two groups were matched for age, body mass index (BMI) and AHI. Among them 22 with COPD and AHI > or = 10 were tested for the chemo-responsiveness to isocapnic hypoxia and hypercapnia. RESULTS: Among the 300 patients with stable COPD, 79 had AHI over 10, meeting the diagnostic criteria of overlap syndrome (OS). Analysis of the polysomnography found that 32 cases (40%) with OS had more hypoventilation lasting over 1 min during sleep. Compared to patients with SAHS only, OS patients had higher percentage of hypopnea index over AHI [(69 +/- 30)% vs (52 +/- 31)%] and a higher percentage of total hypopnea time over total time of sleep apnea and hypopnea [(15 +/- 12)% vs (12 +/- 10)%]. OS patients also had lower hypoxic [(-0.11 +/- 0.05) vs (-0.35 +/- 0.24) L.min(-1).%(-1)] and hypercapnic responses [(1.1 +/- 0.8) vs (1.6 +/- 0.8) L.min(-1).mm Hg(-1) (1 mm Hg = 0.133 kPa)]. CONCLUSION: Patients with both COPD and SAHS had more episodes of hypopnea and hypoventilation during sleep, and had depressed chemo-responsiveness to hypoxia during wakefulness.

[Lung transplantation in the treatment of ventilator dependent end-stage lung diseases: report of three cases].

OBJECTIVE: To investigate the perioperative management, recipient selection of end-stage lung diseases dependent on ventilator, and the strategy of ventilator weaning. METHODS: Fifteen patients underwent lung transplantation in our hospital from 2002 to 2005. Of them, three were dependent on ventilator for 89, 120 and 107 days respectively because of end-stage pulmonary emphysema before operation. Single-lung transplantation was performed in one patient and sequential bilateral single-lung transplantations were performed in two patients without extracorporeal circulation. RESULTS: The three patients were weaned from ventilator in the sixth, eleventh and twenty second day respectively after operation. They were discharged from hospital 71 d, 41 d, and 67 d respectively after operation. They had been followed up for 22, 4, and 2 months respectively before this analysis. Their quality of life improved significantly. CONCLUSION: Lung transplantation is effective for the treatment of ventilator dependent end-stage lung diseases.