Down-phase auditory stimulation is not able to counteract pharmacologically or physiologically increased sleep depth in traumatic brain injury rats

Modulation of slow-wave activity, either via pharmacological sleep induction by administering sodium oxybate or sleep restriction followed by a strong dissipation of sleep pressure, has been associated with preserved posttraumatic cognition and reduced diffuse axonal injury in traumatic brain injury rats. Although these classical strategies provided promising preclinical results, they lacked the specificity and/or translatability needed to move forward into clinical applications. Therefore, we recently developed and implemented a rodent auditory stimulation method that is a scalable, less invasive and clinically meaningful approach to modulate slow-wave activity by targeting a particular phase of slow waves. Here, we assessed the feasibility of down-phase targeted auditory stimulation of slow waves and evaluated its comparative modulatory strength in relation to the previously employed slow-wave activity modulators in our rat model of traumatic brain injury. Our results indicate that, in spite of effectively reducing slow-wave activity in both healthy and traumatic brain injury rats via down-phase targeted stimulation, this method was not sufficiently strong to counteract the boost in slow-wave activity associated with classical modulators, nor to alter concomitant posttraumatic outcomes. Therefore, the usefulness and effectiveness of auditory stimulation as potential standalone therapeutic strategy in the context of traumatic brain injury warrants further exploration

Thalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage immunomodulatory therapy in patients with relapsed and refractory multiple myeloma

The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to the TD regimen may improve the response rate in patients with relapsed or refractory myeloma

Improved functional and histochemical outcomes in l-DOPA plus tolcapone treated VMAT2-deficient mice

Parkinson disease is typically treated with L-3,4-dihydroxyphenylalanine (or levodopa) co-prescribed with concentration stabilizers to prevent undesired motor fluctuations. However, the beneficial role of the chronic combined therapy on disease progression has not been thoroughly explored. We hypothesized that tolcapone, a catechol-O-methyl-transferase inhibitor, co-administered with levodopa may offer beneficial long-term disease-modifying effects through its dopamine stabilization actions. Here, we followed vesicular monoamine transporter 2-deficient and wild-type mice treated twice daily per os with vehicle, levodopa (20 mg/kg), tolcapone (15 mg/kg) or levodopa (12.5 mg/kg) + tolcapone (15 mg/kg) for 17 weeks. We assessed open field, bar test and rotarod performances at baseline and every 4th week thereafter, corresponding to OFF-medication weeks. Finally, we collected coronal sections from the frontal caudate-putamen and determined the reactivity level of dopamine transporter. Vesicular monoamine transporter 2-deficient mice responded positively to chronic levodopa + tolcapone intervention in the bar test during OFF-periods. Neither levodopa nor tolcapone interventions offered significant improvements on their own. Similarly, chronic levodopa + tolcapone intervention was associated with partially rescued dopamine transporter levels, whereas animals treated solely with levodopa or tolcapone did not present this effect. Interestingly, 4-month progression of bar test scores correlated significantly with dopamine-transporter-label density. Overall, we observed a moderate functional and histopathological improvement effect by chronic dopamine replacement when combined with tolcapone in vesicular monoamine transporter 2-deficient mice. Altogether, chronic stabilization of dopamine levels by catechol-O-methyl-transferase inhibition, besides its intended immediate actions, arises as a potential long-term beneficial approach during the progression of Parkinson disease

Novel rat model of weight drop-induced closed diffuse traumatic brain injury compatible with electrophysiological recordings of vigilance states

Traumatic brain injury (TBI) is a major cause of persistent disabilities such as sleep-wake disorders (SWD). However, rodent studies of SWD after TBI are scarce due to lack of appropriate TBI models reproducing acceleration-deceleration forces and compatible with electroencephalography/myography (EEG/EMG)-based recordings of vigilance states. We therefore adapted Marmarou's impact acceleration model to allow for compatibility with EEG-headset implantation. Following implantation of EEG/EMG electrodes, we induced closed TBI by a frontal, angular hit with a weight-drop device (44 rats, weight 2500g, fall height 25cm). Subsequently, we tested our model's usefulness for long-term studies on a behavioral, electrophysiological and histological level. Neurological, motor and memory deficits were assessed with the neurological severity score, open field, and novel object recognition tests, respectively. EEG/EMG recordings were performed in both SHAM (n=7) and TBI (n=7) rats before and 1, 7 and 28 days after trauma to evaluate sleep-wake proportions and posttraumatic implant stability. Histological assessments included hematoxylin and eosin staining for parenchymal damage and hemorrhage and amyloid precursor protein staining for diffuse axonal damage. All rats survived TBI without major neurological or motor deficits. Memory function was impaired after TBI at weeks 1, 2, 3 and recovered at week 4. EEG implants were stable for at least 1 month and enabled qualitative and quantitative sleep analyses. Histological assessments revealed no major bleedings or necrosis but intense diffuse axonal damage following TBI. In conclusion, this approach fulfills major preconditions for experimental TBI models and offers a possibility to electrophysiologically study behavioral states before and after trauma

Increased Sleep Need and Reduction of Tuberomammillary Histamine Neurons after Rodent Traumatic Brain Injury

Although sleep-wake disturbances are prevalent and well described after traumatic brain injury, their pathophysiology remains unclear, most likely because human traumatic brain injury is a highly heterogeneous entity that makes the systematic study of sleep-wake disturbances in relation to trauma-induced histological changes a challenging task. Despite increasing interest, specific and effective treatment strategies for post-traumatic sleep-wake disturbances are still missing. With the present work, therefore, we aimed at studying acute and chronic sleep-wake disturbances by electrophysiological means, and at assessing their histological correlates after closed diffuse traumatic brain injury in rats with the ultimate goal of generating a model of post-traumatic sleep-wake disturbances and associated histopathological findings that accurately represents the human condition. We assessed sleep-wake behavior by means of standard electrophysiological recordings before and 1, 7, and 28 days after sham or traumatic brain injury procedures. Sleep-wake findings were then correlated to immunohistochemically labeled and stereologically quantified neuronal arousal systems. Compared with control animals, we found that closed diffuse traumatic brain injury caused increased sleep need one month after trauma, and sleep was more consolidated. As histological correlate, we found a reduced number of histamine immunoreactive cells in the tuberomammillary nucleus, potentially related to increased neuroinflammation. Monoaminergic and hypocretinergic neurotransmitter systems in the hypothalamus and rostral brainstem were not affected, however. These results suggest that our rat traumatic brain injury model reflects human post-traumatic sleep-wake disturbances and associated histopathological findings very accurately, thus providing a study platform for novel treatment strategies for affected patients