Amelioration of olfactory dysfunction in a mouse model of Parkinson's disease via enhancing GABAergic signaling.

BACKGROUND: Olfactory dysfunction is among the earliest non-motor symptoms of Parkinson's disease (PD). As the foremost pathological hallmark, α-synuclein initiates the pathology in the olfactory pathway at the early stage of PD, particularly in the olfactory epithelium (OE) and olfactory bulb (OB). However, the local neural microcircuit mechanisms underlying olfactory dysfunction between OE and OB in early PD remain unknown. RESULTS: We observed that odor detection and discrimination were impaired in 6-month-old SNCA-A53T mice, while their motor ability remained unaffected. It was confirmed that α-synuclein increased and accumulated in OB but not in OE. Notably, the hyperactivity of mitral/tufted cells and the excitation/inhibition imbalance in OB were found in 6-month-old SNCA-A53T mice, which was attributed to the impaired GABAergic transmission and aberrant expression of GABA transporter 1 and vesicular GABA transporter in OB. We further showed that tiagabine, a potent and selective GABA reuptake inhibitor, could reverse the impaired olfactory function and GABAergic signaling in OB of SNCA-A53T mice. CONCLUSIONS: Taken together, our findings demonstrate potential synaptic mechanisms of local neural microcircuit underlying olfactory dysfunction at the early stage of PD. These results highlight the critical role of aberrant GABAergic signaling of OB in early diagnosis and provide a potential therapeutic strategy for early-stage PD.

Anticonvulsant Effect of Swertiamarin Against Pilocarpine-Induced Seizures in Adult Male Mice.

Epilepsy is one of the common and major neurological disorders, approximately a third of the individuals with epilepsy suffer from seizures and not able to successfully respond to available medications. Current study was designed to investigate whether Swertiamarin (Swe) had anticonvulsant activity in the pilocarpine (PILO)-treated mice. Thirty minutes prior to the PILO (280 mg/kg) injection, the mice were administrated with Swe (50, 150, and 450 mg/kg) and valproate sodium (VPA, 200 mg/kg) once. Seizures and electroencephalography (EEG) were observed, and then the mice were killed for Nissl, Fluoro-jade B (FJB) staining. Astrocytic activation was examined in the hippocampus. Western blot analysis was used to examine the expressions of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10). The results indicated that pretreatment with Swe (150, 450 mg/kg) and VPA (200 mg/kg) significantly delayed the onset of the first convulsion and reduced the incidence of status epilepticus and mortality. Analysis of EEG recordings demonstrated that Swe (150, 450 mg/kg) and VPA (200 mg/kg) sharply decreased epileptiform discharges. Furthermore, Nissl and FJB staining revealed that Swe (150, 450 mg/kg) and VPA (200 mg/kg) relieved the neuronal damage. Additionally, Swe (450 mg/kg) dramatically inhibited astrocytic activation. Western blot analysis showed that Swe (450 mg/kg) significantly decreased the expressions of IL-1ß, IL-6, TNF-α and elevated the expression of IL-10. Taken together, these findings revealed that Swe exerted anticonvulsant effects on PILO-treated mice. Further studies are encouraged to investigate these beneficial effects of Swe as an adjuvant in epilepsy.

The Anticonvulsant and Neuroprotective Effects of Oxysophocarpine on Pilocarpine-Induced Convulsions in Adult Male Mice.

Epilepsy is one of the prevalent and major neurological disorders, and approximately one-third of the individuals with epilepsy experience seizures that do not respond well to available medications. We investigated whether oxysophocarpine (OSC) had anticonvulsant and neuroprotective property in the pilocarpine (PILO)-treated mice. Thirty minutes prior to the PILO injection, the mice were administrated with OSC (20, 40, and 80 mg/kg) once. Seizures and electroencephalography (EEG) were observed, and then the mice were killed for Nissl and Fluoro-jade B (FJB) staining. The oxidative stress was measured at 24 h after convulsion. Western blot analysis was used to examine the expressions of the Bax, Bcl-2, and Caspase-3. In this study, we found that pretreatment with OSC (40, 80 mg/kg) significantly delayed the onset of the first convulsion and status epilepticus (SE) and reduced the incidence of SE and mortality. Analysis of EEG recordings revealed that OSC (40, 80 mg/kg) significantly reduced epileptiform discharges. Furthermore, Nissl and FJB staining showed that OSC (40, 80 mg/kg) attenuated the neuronal cell loss and degeneration in hippocampus. In addition, OSC (40, 80 mg/kg) attenuated the changes in the levels of Malondialdehyde (MDA) and strengthened glutathione peroxidase and catalase activity in the hippocampus. Western blot analysis showed that OSC (40, 80 mg/kg) significantly decreased the expressions of Bax, Caspase-3 and increased the expression of Bcl-2. Collectively, the findings of this study indicated that OSC exerted anticonvulsant and neuroprotective effects on PILO-treated mice. The beneficial effects should encourage further studies to investigate OSC as an adjuvant in epilepsy, both to prevent seizures and to protect neurons in brain.