Acute single dose of ketamine relieves mechanical allodynia and consequent depression-like behaviors in a rat model.

Both chronic pain and depression are debilitating diseases, which often coexist in clinic. However, current analgesics and antidepressants exhibit limited efficacy for this comorbidity. The present study aimed to investigate the effect of ketamine on the comorbidity of inflammatory pain and consequent depression-like behaviors in a rat model established by intraplantar administration of complete Freunds adjuvant (CFA). The mechanical withdrawal threshold, thermal withdrawal latency, open field test, forced swimming test, and sucrose preference test were evaluated after the CFA injection and ketamine treatment. The hippocampus was harvested to determine the levels of interleukin (IL)-6, IL-1ß, indoleamine 2,3-dioxygenase (IDO), kynurenine (KYN), 5-hydroxytryptamine (5-HT), and tryptophan (TRP). The inflammatory pain-induced depression-like behaviors presented on 7days and lasted to at least 14days after the CFA injection. Single dose of ketamine at 20mg/kg relieved both the mechanical allodynia and the associated depression-like behaviors as demonstrated by the attenuated mechanical withdrawal threshold, reduced immobility time in the forced swim test, and increased sucrose preference after ketamine treatment. The total distance had no significant change after the CFA injection or ketamine treatment in the open field test. Simultaneously, ketamine reduced the levels of IL-6, IL-1ß, IDO, and KYN/TRP ratio and increased the 5-HT/TRP ratio in the hippocampus. In conclusion, acute single dose of ketamine can rapidly attenuate mechanical allodynia and consequent depression-like behaviors and down-regulate hippocampal proinflammatory responses and IDO/KYN signal pathway in rats.

Tert-butylhydroquinone Ameliorates Early Brain Injury After Experimental Subarachnoid Hemorrhage in Mice by Enhancing Nrf2-Independent Autophagy.

Evidence has shown that the activation of the autophagy pathway after experimental subarachnoid hemorrhage (SAH) protects against neuronal damage. Tert-butylhydroquinone (tBHQ), a commonly used nuclear factor erythroid 2-related factor 2 (Nrf2) activator, was found to significantly enhance autophagy activation. The aim of this study was to explore the effect of tBHQ treatment on early stage brain injury at 24 h after SAH. The results showed that tBHQ treatment failed to stimulate an effective anti-oxidative effect at 24 h after the SAH operation, but succeeded in ameliorating early brain injury, including alleviated brain edema, BBB disruption, neuronal degeneration and neurological deficits. Further exploration found that tBHQ treatment significantly increased the expression of Beclin-1 and the ratio of microtubule-associated protein 1 light chain 3 (LC3)-II to LC3-I, suggesting that autophagy was enhanced after tBHQ treatment. Moreover, tBHQ treatment restored Bcl-2 and Bax expression and reduced caspase-3 cleavage, suggesting the protective effect of tBHQ treatment in ameliorating brain injury after SAH. Furthermore, tBHQ enhanced autophagy activation, decreased neuronal degeneration and improved the neurological score after SAH in Nrf2-deficient mice. Taken together, these findings suggest that tBHQ treatment exerts neuro-protective effects against EBI following SAH by enhancing Nrf2-independent autophagy. Therefore, tBHQ is a promising therapeutic agent against EBI following SAH.

Zinc as mediator of ubiquitin conjugation following traumatic brain injury.

Previous studies have shown that pathological zinc accumulation and deposition of ubiquitinated protein aggregates are commonly detected in many acute neural injuries, such as trauma, epilepsy and ischemia. However, the underlying mechanisms are poorly understood. Here we assessed the effect of zinc on ubiquitin conjugation and subsequent neurodegeration following traumatic brain injury (TBI). First, we found that scavenging endogenous Zn(2+) reduced trauma-induced ubiquitin conjugation and protected neurons from TBI insults in rat hippocampus. Second, we detected both zinc accumulation and increased ubiquitin conjugated protein following brain trauma in human cortical neurons. Our previous study has shown that zinc can induce ubiquitin conjugation in cultured hippocampal neurons. All these findings indicate that alterations in Zn(2+) homeostasis may impair the protein degradation pathway and ultimately cause neuronal injury following traumatic brain injury.

The expression of PGC-1α in the mice brain after traumatic brain injury.

BACKGROUND: Peroxisome proliferator activated receptor γ co-activator-1α (PGC-1α) is a transcriptional co-activator that co-ordinately regulates genes required for mitochondrial biogenesis and is a key contributor to the up-regulation of antioxidant activities in response to oxidative stress. The expression pattern of PGC-1α after traumatic brain injury (TBI) has not been studied. MATERIALS AND METHODS: Ninety male ICR mice (28-32 g) were randomly assigned to six groups: sham, 3, 6, 12, 24 and 48 hours after TBI. PGC-1α mRNA levels in mice brain were detected by reverse-transcriptase polymerase chain reaction and its nuclear protein levels by Western blot from 3-48 hours after TBI. PGC-1α distribution in the cerebral cortex after TBI was investigated by immunohistochemistry. MAIN OUTCOMES AND RESULTS: The PGC-1α mRNA level significantly increased from 3 hours after TBI, peaked at 6 hours and gradually decreased from 12 to 48 hours. The nuclear PGC-1α protein level increased from 6 to 24 hours after TBI and decreased at 48 hours after TBI. Increased PGC-1α immunostaining was detected in the neurons of the cerebral cortex at 12 hours after TBI. CONCLUSION: PGC-1α may play an important role in the brain after TBI.

[Resting functional MRI with default mode-based functional connectivity analysis for localization of epileptic activity].

OBJECTIVE: Using the functional connectivity analysis based on the underlying neurophysiological characteristic that epileptic discharges can induce change of brain default mode, to develop a technique for epileptogenic localization using functional MRI (fMRI) without simultaneous electroencephalography (EEG). METHODS: A data-driven method that jointly employed independent component analysis and functional connectivity analysis was used for the resting functional MRI data analysis of 12 focal epileptic patients. The independent components were ranged according to the coefficients of the negative correlation between independent component time course and the signal temporal course in the region of posterior cingulate cortex. The results were comparatively studied with simultaneous EEG-fMRI. RESULTS: In the 10 successful results from 12 patients underwent EEG-fMRI examination, the outcomes of eight subjects were concordant with pathological foci. While the results of all 10 patients processed by data-driven method were concordant with pathological foci, besides the other patients who failed to perform EEG-fMRI examination. Meanwhile, the default mode was well mapped in all patients. CONCLUSIONS: The default mode-based functional connectivity analysis can localize the epileptogenic foci effectively without simultaneous EEG, besides to detect the default mode of epileptic patients.