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

Abstract

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-1β, and IL-6 were reduced in the LEV-L and LEV-H groups, and IL-1β 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-1β 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.

Actigraphy Analysis of Sleep Associates with Salivary IL-6 Concentration in Institutionalized Older Individuals

“…Changes in color intensity and absorbance at 450 nm and 490 nm were read using the ELISA microplate reader, and a standard curve was prepared by plotting the absorbance readings of the standards against their concentration. Since several common comorbidities in older individuals are associated with an increase in inflammatory markers, including IL-6, such as arterial hypertension [ 26 ], chronic obstructive pulmonary disease [ 27 ], diabetes [ 28 , 29 ], dyslipidemia [ 30 ], or osteoarthritis [ 31 , 32 ], we evaluated whether salivary IL-6 differ based on the presence or absence of these comorbidities. Since anxiety and depression are common psychiatric disorders in this population, we also analyzed whether there was a significant association with these comorbidities, which have also been linked to altered IL-6 level [ 33 , 34 ].…”

Risk assessment of arrhythmias related to three antiseizure medications: a systematic review and single-arm meta-analysis

“…As a newer ASM, LEV is emerging as a versatile drug compared to metformin and aspirin. It has been used for the treatment of epilepsy, pain, ulcerative colitis, and Parkinson's disease, as well as cognitive and psychiatric disorders, and therefore its side effects deserve our attention (14)(15)(16)(17). LCM enhances slow sodium channel inactivation in both the brain and heart, which reduces the channel availability over a long period, particularly during epileptic seizures, and reduces interictal discharges (18).…”