Relative D3 vitamin deficiency and consequent cognitive impairment in an animal model of Alzheimer's disease: Potential involvement of collapsin response mediator protein-2.

Alzheimer's disease (AD) starts with memory impairments that can be observed before the appearance of significant neuropathology; thus, identifying mechanisms to stop AD progression is an urgent priority. Epidemiological and clinical data show that the consequences of vitamin D deficiency are relevant to disease risk and can be observed in the progression of many diseases, especially AD, whereas higher serum levels of vitamin D are associated with better cognitive test performance. However, the potential therapeutic strategy and underlying mechanisms of vitamin D supplementation against AD still need to be further investigated. In the present study, we found that 3xTg-AD mice with vitamin D supplementation exhibited an increase in serum vitamin D concentrations and improved cognition. We measured serum vitamin D binding protein (VDBP) concentrations and found that serum VDBP levels were increased in 3xTg-AD mice compared to B6129S control mice, but there was no significant difference between control- and vitamin D-treated 3xTg-AD groups. The vitamin D-mediated memory improvement may be accompanied by the suppression of increased hippocampal collapsin response mediator protein-2 (CRMP2) phosphorylation, and the restoration of CRMP2 phosphorylation by okadaic acid (OA) could abolish the beneficial effects of vitamin D. In addition, we found that CRMP2 was associated with NR2B and PSD-95 in 3xTg-AD mice with vitamin D supplementation. This CRMP2-NR2B interaction could be disrupted by a TAT-CBD3 peptide or OA, leading to attenuated memory protection in vitamin D-treated 3xTg-AD mice. Therefore, CRMP2 may be involved in vitamin D-mediated memory improvement in AD.

Hyperbaric Oxygen Effects on Depression-Like Behavior and Neuroinflammation in Traumatic Brain Injury Rats.

OBJECTIVE: The aim of this study was to determine whether hyperbaric oxygen (HBO) therapy causes attenuation of traumatic brain injury (TBI)-induced depression-like behavior and its associated anti-neuroinflammatory effects after fluid percussion injury. METHODS: Anesthetized male Sprague-Dawley rats were divided into 3 groups: sham operation plus normobaric air (NBA) (21% oxygen at 1 absolute atmosphere [ATA]), TBI plus NBA, and TBI plus HBO (100% oxygen at 2.0 ATA). HBO was applied immediately for 60 min/d after TBI for 3 days. Depression-like behavior was tested by a forced swimming test, motor function was tested by an inclined plane test, and infarction volume was tested by triphenyltetrazolium chloride (TTC) staining on days 4, 8, and 15. Neuronal apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling assay), microglial (marker OX42) activation, and tumor necrosis factor (TNF)-α expression in microglia in the hippocampus CA3 were measured by immunofluorescence methods. RESULTS: Compared with the TBI controls, without significant changes in TTC staining or in the motor function test, TBI-induced depression-like behavior was significantly attenuated by HBO therapy by day 15 after TBI. Simultaneously, TBI-induced neuronal apoptosis, microglial (marker OX42) activation, and TNF-α expression in the microglia in the hippocampus CA3 were significantly reduced by HBO. CONCLUSIONS: Our results suggest that HBO treatment may ameliorate TBI-induced depression-like behavior in rats by attenuating neuroinflammation, representing one possible mechanism by which depression-like behavior recovery might occur. We also recommend HBO as a potential treatment for TBI-induced depression-like behavior if early intervention is possible.

Early electroacupuncture treatment ameliorates neuroinflammation in rats with traumatic brain injury.

BACKGROUND: Neuroinflammation is the leading cause of neurological sequelae after traumatic brain injury (TBI). The aim of the present study was to investigate whether the neuroprotective effects of electroacupuncture (EA) are mediated by anti-neuroinflammatory effects in a rat model of TBI. METHODS: Male Sprague-Dawley rats were randomly divided into three groups: sham-operated, TBI control, and EA-treated. The animals in the sham-operated group underwent a sham operation, those in the TBI control group were subjected to TBI, but not EA, and those in the EA group were treated with EA for 60 min immediately after TBI, daily for 3 consecutive days. EA was applied at the acupuncture points GV20, GV26, LI4, and KI1, using a dense-dispersed wave, at frequencies of 0.2 and 1 Hz, and an amplitude of 1 mA. Cell infarction volume (TTC stain), neuronal apoptosis (markers: TUNEL and Caspase-3), activation of microglia (marker: Iba1) and astrocytes (marker: GFAP), and tumor necrosis factor (TNF)-α expression in the microglia and astrocytes were evaluated by immunofluorescence. Functional outcomes were assessed using the inclined plane test. All tests were performed 72 h after TBI. RESULTS: We found that TBI-induced loss of grasp strength, infarction volume, neuronal apoptosis, microglial and astrocyte activation, and TNF-α expression in activated microglia and astrocytes were significantly attenuated by EA treatment. CONCLUSIONS: Treatment of TBI in the acute stage with EA for 60 min daily for 3 days could ameliorate neuroinflammation. This may thus represent a mechanism by which functional recovery can occur after TBI.

Hyperbaric oxygen effects on neuronal apoptosis associations in a traumatic brain injury rat model.

BACKGROUND: The neuroprotective mechanisms of hyperbaric oxygen (HBO) therapy on traumatic brain injury (TBI) remain unclear, especially neuronal apoptosis associations such as the expression of tumor necrosis factor alpha (TNF-α), transforming growth-interacting factor (TGIF), and TGF-ß1 after TBI. The aim of this study was to investigate the neuroprotective effects of HBO therapy in a rat model of TBI. MATERIALS AND METHODS: The experimental rats were randomly divided into three groups as follows: TBI + normobaric air (21% O2 at one absolute atmosphere), TBI + HBO, and sham-operated normobaric air. The TBI + HBO rats received 100% O2 at 2.0 absolute atmosphere for 1 h immediately after TBI. Local and systemic TNF-α expression, neuropathology, levels of the neuronal apoptosis-associated proteins TGIF and TGF-ß1, and functional outcome were evaluated 72 h after the onset of TBI. RESULTS: Compared to the TBI control groups, the running speed of rats on the TreadScan after TBI was significantly attenuated by HBO therapy. The TBI-induced local and systemic TNF-α expression, neuronal damage score, and neuronal apoptosis were also significantly reduced by HBO therapy. Moreover, HBO treatment attenuated the expression of TGIF but increased TGF-ß1 expression in neurons. CONCLUSIONS: We concluded that treatment of TBI with HBO during the acute phase of injury can decrease local and systemic proinflammatory cytokine TNF-α production, resulting in neuroprotective effects. We also suggest that decreased levels of TGIF and increased levels of TGF-ß in the injured cortex leading to decreased neuronal apoptosis is one mechanism by which functional recovery may occur.

Cerebral blood flow and apoptosis-associated factor with electroacupuncture in a traumatic brain injury rat model.

OBJECTIVE: Electroacupuncture (EA) has been widely used for treatment of stroke, but there is little information on the effect of EA on the neuroprotective function in traumatic brain injury (TBI). The aim of the present study was to investigate the protective effects and mechanisms of EA treatment in a TBI rat model. METHODS: Male Sprague-Dawley rats were randomly divided into four groups: sham operation, TBI control, TBI+EA treated for 30 min or TBI+EA treated for 60 min. The animals were treated with EA immediately after TBI. The EA was applied at acupuncture points GV20, GV26, LI4 and KI1 with a dense-dispersed wave, frequencies of 0.2 and 1 Hz, and amplitude of 1 mA for 30 or 60 min. Regional blood flow, cell infarction volume, extent of neuronal apoptosis, expression of cell apoptosis-associated factor transforming growth-interacting factor (TGIF) were studied, and functional outcome was assessed by running speed test. All tests except regional blood flow were performed 72 h after TBI onset. RESULTS: Immediately after TBI, compared with the TBI control groups, the regional blood flow was significantly increased by EA treatment for 60 min. Compared with the TBI controls 72 h after TBI, the TBI-induced run speed impairment, infarction volume, neuronal apoptosis and apoptosis-associated TGIF expression were significantly improved by EA treatment. CONCLUSIONS: The treatment of TBI in the acute stage with EA for 60 min could increase the regional blood flow and attenuate the levels of TGIF in the injured cortex, might lead to a decrease in neuronal apoptosis and cell infarction volume, and might represent one mechanism by which functional recovery may occur.

Microglial activation induced by traumatic brain injury is suppressed by postinjury treatment with hyperbaric oxygen therapy.

BACKGROUND: The mechanisms underlying the protective effects of hyperbaric oxygen (HBO) therapy on traumatic brain injury (TBI) are unclear. TBI initiates a neuroinflammatory cascade characterized by activation of microglia and increased production of proinflammatory cytokines. In this study, we attempted to ascertain whether the occurrence of neuroinflammation exhibited during TBI can be reduced by HBO. METHODS: TBI was produced by the fluid percussion technique in rats. HBO (100% O2 at 2.0 absolute atmospheres) was then used at 1 h (HBO I) or 8 h (HBO II) after TBI. Neurobehavior was evaluated by the inclined plane test on the 72 h after TBI and then the rats were killed. The infarction area was evaluated by Triphenyltetrazolium chloride. Immunofluorescence staining was used to evaluate neuronal apoptosis (TUNEL + NeuN), microglial cell aggregation count (OX42 + DAPI), and tumor necrosis factor-alpha (TNF-α) expression in microglia cell (OX42 + TNF-α). RESULTS: The maximum grasp angle in the inclined plane test and cerebral infarction of the rats after TBI were significantly attenuated by HBO therapy regardless of whether the rats were treated with HBO 1 or 8 h after TBI compared with the controls. TBI-induced microglial activation, TNF-α expression, and neuronal apoptosis were also significantly reduced by HBO therapy. CONCLUSIONS: Our results demonstrate that treatment of TBI during the acute phase of injury can attenuate microgliosis and proinflammatory cytokine TNF-α expression resulting in a neuroprotective effect. Even treating TBI with HBO after 8 h had a therapeutic effect.

Therapeutic evaluation of etanercept in a model of traumatic brain injury.

Antagonism of tumor necrosis factor-alpha with etanercept has proved to be effective in the treatment of spinal cord injury and centrally endotoxin-induced brain injury. However, etanercept may offer promise as therapy for traumatic brain injury (TBI). In this study, anesthetized rats, immediately after the onset of TBI, were divided into two major groups and given the vehicle solution (1 mL/kg of body weight) or etanercept (5 mg/kg of body weight) intraperitoneally once per 12 h for consecutive 3 days. Etanercept caused attenuation of TBI-induced cerebral ischemia (e.g., increased cellular levels of glutamate and lactate-to-pyruvate ratio), damage (e.g., increased cellular levels of glycerol) and contusion and motor and cognitive function deficits. TBI-induced neuronal apoptosis (e.g., increased numbers of terminal deoxynucleotidyl transferase αUTP nick-end labeling and neuronal-specific nuclear protein double-positive cells), glial apoptosis (e.g., increased numbers of terminal deoxynucleotidyl transferase αUTP nick-end labeling and glial fibrillary acidic protein double-positive cells), astrocytic (e.g., increased numbers of glial fibrillary acidic protein positive cells) and microglial (e.g., increased numbers of ionized calcium-binding adapter molecule 1-positive cells) activation and activated inflammation (e.g., increased levels of tumor necrosis factor-alpha, interleukin-1ß and interleukin-6) were all significantly reduced by etanercept treatment. These findings suggest that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats.

Acute paraplegia following chiropractic therapy.

We report a 44-year-old man suffering complete paraplegia due to paraspinal and epidural abscess, following chiropractic therapy for severe back pain and whose diagnosis was delayed. He received an immediate laminectomy from T3 through T6 to decompress the full extent of the abscess and appropriate antibiotic therapy for 4 weeks postoperatively for the identified microorganism (Staphylococcus aureus). After 3 months of rehabilitation, he had recovered bladder function with moderate left lower extremity paresis. We emphasise the importance of urgent spinal gadolinium-enhanced MRI in those patients with localised back pain and raised inflammatory markers (including erythrocyte sedimentation rate). Furthermore, it is necessary to be aware of the risk of acute paraplegia after forceful massage to the back.