Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury.

Melatonin receptors (MTs) are potential drug targets for stroke therapy. Ramelteon is a selective melatonin receptor agonist used to treat insomnia. In this study we investigated whether ramelteon could attenuate cerebral ischemia in mice. Acute focal cerebral ischemia was induced in mice via middle cerebral artery occlusion (MCAO). We found oral administration of ramelteon (3.0 mg/kg) significantly attenuated ischemic injury even when it was given 4 h after the onset of ischemia. We showed that administration of ramelteon (3.0 mg/kg) displayed comparable protective efficacy and length of effective time window as administration of edaravone (10 mg/kg, i.p.), which was used in clinic to treat ischemic stroke. Chronic ischemic brain injury was induced in mice using photothrombosis. Oral administration of ramelteon (3.0 mg · kg-1 · d-1) for 7 days after ischemia significantly attenuated functional deficits for at least 15 days. The neuroprotection of ramelteon was blocked by 4-P-PDOT, a specific MT antagonist. We further revealed that ramelteon significantly inhibited autophagy in the peri-infarct cortex in both the mouse ischemia models via regulating AMPK/mTOR signaling pathway. Intracerebroventricular injection of rapamycin, an autophagy activator, compromised the neuroprotection of ramelteon, suggesting ramelteon might attenuate ischemic injury by counteracting autophagic cell death. These data demonstrate for the first time the potential benefits of ramelteon in the treatment of both acute and chronic ischemic brain injury and provide the rationale for the application of ramelteon in stroke therapy.

[Effects of cysteinyl leukotrienes receptor antagonists on chronic brain injury after global cerebral ischemia/reperfusion].

OBJECTIVE: : To investigate the effects of cysteinyl leukotrienes receptor (CysLTR) antagonists on global cerebral ischemia/reperfusion (CI/R) injury in gerbils, and to explore its mechanism. METHODS: : Totally 40 gerbils weighting 45-65 g were randomized into sham, saline, Pranlukast and HAMI 3379 groups with 10 animals in each. The CI/R model was established in gerbils by bilateral common carotid occlusion for 10 min followed by reperfusion. After ischemia, the CysLTR antagonists Pranlukast (0.1 mg/kg) and HAMI 3379 (0.1 mg/kg) were injected intraperitoneally for 5 consecutive days in the last two groups,while the former two groups were injected with saline only (10 mL/kg). After 24 h or 14 d reperfusion, neurological deficit score was evaluated and the behavioral dysfunction was assessed, respectively. And 14 d after reperfusion, the neuron morphology of cerebral cortex was observed in brain sections stained with Cresyl violet. In addition, the Iba-1 (microgila) and GFAP (astrocyte) positive cells in cerebral cortex were observed by using immunohistochemitry method. RESULTS: : CI/R models were successfully established in 21 out of 30 gerbils with 7 in saline group, 6 in Pranlukast group, and 8 in HAMI 3379 group. Compared with saline group, Pranlukast and HAMI 3379 significantly attenuated neurological deficits, improved the behavioral function 24 h after reperfusion(all P<0.01); Pranlukast and HAMI 3379 also significantly improved the behavioral function 14 days after reperfusion(P<0.05 or P<0.01). Compared with saline group, the neurological symptom scores in Pranlukast and HAMI 3379 groups presented a trend of amelioration 14 d after reperfusion, but it was not significant(P>0.05). In addition, Pranlukast and HAMI 3379 also inhibited the neuron loss and injury, suppressed microgila and astrocyte activation 14 d after reperfusion(all P<0.01). CONCLUSIONS: : CysLTR antagonists Pranlukast and HAMI 3379 have long-term neuroprotective effect on chronic brain injury induced by global cerebral ischemia/reperfusion in gerbils.

Amantadine Did Not Positively Impact Cognition in Chronic Traumatic Brain Injury: A Multi-Site, Randomized, Controlled Trial.

Despite limited evidence to support the use of amantadine to enhance cognitive function after traumatic brain injury (TBI), the clinical use for this purpose is highly prevalent and is often based on inferred belief systems. The aim of this study was to assess effect of amantadine on cognition among individuals with a history of TBI and behavioral disturbance using a parallel-group, randomized, double-blind, placebo-controlled trial of amantadine 100 mg twice-daily versus placebo for 60 days. Included in the study were 119 individuals with two or more neuropsychological measures greater than 1 standard deviation below normative means from a larger study of 168 individuals with chronic TBI (>6 months post-injury) and irritability. Cognitive function was measured at treatment days 0, 28, and 60 with a battery of neuropsychological tests. Composite indices were generated: General Cognitive Index (included all measures), a Learning Memory Index (learning/memory measures), and Attention/Processing Speed Index (attention and executive function measures). Repeated-measures analysis of variance revealed statistically significant between-group differences favoring the placebo group at day 28 for General Cognitive Index (p = 0.002) and Learning Memory Index (p = 0.001), but not Attention/Processing Speed Index (p = 0.25), whereas no statistically significant between-group differences were found at day 60. There were no statistically significant between-group differences on adverse events. Cognitive function in individuals with chronic TBI is not improved by amantadine 100 mg twice-daily. In the first 28 days of use, amantadine may impede cognitive processing. However, the effect size was small and mean scores for both groups were generally within expectations for persons with history of complicated mild-to-severe TBI, suggesting that changes observed across assessments may not have functional significance. The use of amantadine to enhance cognitive function is not supported by these findings.

Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats.

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is associated with high morbidity and mortality. Inflammation has been considered as the major contributor to brain damage after SAH. SAH induces a systemic increase in pro-inflammatory cytokines and chemokines. Disruption of blood-brain barrier (BBB) facilitates the influx of inflammatory cells. It has been reported that the activation of toll-like receptor 4 (TLR4)/NF-κB signaling pathway plays a vital role in the central nervous system diseases. Apigenin, a common plant flavonoid, possesses anti-inflammation effect. In this study, we focused on the effects of apigenin on EBI following SAH and its anti-inflammation mechanism. Our results showed that apigenin (20mg/kg) administration significantly attenuated EBI (including brain edema, BBB disruption, neurological deficient, severity of SAH, and cell apoptosis) after SAH in rats by suppressing the expression of TLR4, NF-κB and their downstream pro-inflammatory cytokines in the cortex and by up-regulating the expression of tight junction proteins of BBB. Double immunofluorescence staining demonstrated that TLR4 was activated following SAH in neurons, microglia cells, and endothelial cells but not in astrocytes. Apigenin could suppress the activation of TLR4 induced by SAH and inhibit apoptosis of cells in the cortex. These results suggested that apigenin could attenuate EBI after SAH in rats by suppressing TLR4-mediated inflammation and protecting against BBB disruption.

Magnesium in acute and chronic brain injury: an update.

While brain free magnesium levels have been shown to decline in a number of acute and chronic brain pathologies, the mechanisms of such decline and the potential for magnesium administration as a therapeutic intervention are still unclear. In acute brain injury, magnesium therapy has failed in recent clinical trials of trauma, presumably because of an intact blood brain barrier at the time of administration reducing central penetration. Under such conditions, magnesium's peripheral effects on cardiovascular parameters may dominate over the central, and potentially neuroprotective, effects of the compound. In contrast, magnesium has been demonstrated to be beneficial in lacunar strokes, albeit that recent animal studies indicate that this effect is without any significant reduction of lesion size. Postnatal magnesium has also been shown to improve neurological outcome in term neonates with perinatal asphyxia, although this may be limited to cases of mild to moderate brain injury; no effect is observed following severe brain injury. Prenatal magnesium has been reported to be beneficial for outcome in very preterm infants, although this may only be at low doses. Combination therapies are also showing promise in experimental studies, with combined magnesium and mild hypothermia as well as magnesium and polyethylene glycol proving effective in ischemic stroke and in spinal cord injury, respectively. With respect to chronic brain injury, recent results indicate that magnesium deficient mice are susceptible to developing Parkinson's disease, which is consistent with earlier findings that magnesium deficiency over a number of generations is associated with the development of Parkinson's disease. The latter was associated with the appearance of variants of the TRPM channels. Our recent studies have shown that Parkinson's disease is associated with reduced TRPM2 and TRPM7 channel mRNA expression. Taken together, a more complete picture is emerging of the role of magnesium in brain injury, its therapeutic potential as well the mechanisms associated with its decline.

White matter tract injury and cognitive impairment in human immunodeficiency virus-infected individuals.

Approximately half of those infected with the human immunodeficiency virus (HIV) exhibit cognitive impairment, which has been related to cerebral white matter damage. Despite the effectiveness of antiretroviral treatment, cognitive impairment remains common even in individuals with undetectable viral loads. One explanation for this may be subtherapeutic concentrations of some antiretrovirals in the central nervous system (CNS). We utilized diffusion tensor imaging and a comprehensive neuropsychological evaluation to investigate the relationship of white matter integrity to cognitive impairment and antiretroviral treatment variables. Participants included 39 HIV-infected individuals (49% with acquired immunodeficiency syndrome [AIDS]; mean CD4 = 529) and 25 seronegative subjects. Diffusion tensor imaging indices were mapped onto a common whole-brain white matter tract skeleton, allowing between-subject voxelwise comparisons. The total HIV-infected group exhibited abnormal white matter in the internal capsule, inferior longitudinal fasciculus, and optic radiation; whereas those with AIDS exhibited more widespread damage, including in the internal capsule and the corpus callosum. Cognitive impairment in the HIV-infected group was related to white matter injury in the internal capsule, corpus callosum, and superior longitudinal fasciculus. White matter injury was not found to be associated with HIV viral load or estimated CNS penetration of antiretrovirals. Diffusion tensor imaging was useful in identifying changes in white matter tracts associated with more advanced HIV infection. Relationships between diffusion alterations in specific white matter tracts and cognitive impairment support the potential utility of diffusion tensor imaging in examining the anatomical underpinnings of HIV-related cognitive impairment. The study also confirms that CNS injury is evident in persons infected with HIV despite effective antiretroviral treatment.

Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8.

Certain effects of melatonin on senescence were investigated. The experimental model used was 10-month-old senescence-accelerated mouse prone 8 (SAMP8). The mice in the experiment were administered melatonin (10 mg/kg) from the age of 1 month. Results showed that chronic administration of melatonin decreased cell loss in the cerebral cortex and reduced oxidative damage in protein and lipids. There are several studies suggesting that the activation of the cdk5/p35 pathway at its cleavage to cdk5/p25 may play a role in hyperphosphorylation of tau during aging and neurodegenerative diseases. Melatonin not only reduced the cerebral aging disturbances, but also prevented tau hyperphosphorylation present in the experimental model used in this study. Melatonin reduced cdk5 expression, as well as the cleavage of p35 to p25. The other tau kinase studied, GSK3beta, showed a reduction in this activity in comparison with SAMP8 nontreated SAMP8. These data indicate that melatonin possesses neuroprotective properties against cerebral damage gated to senescence. Moreover, these data suggest that the cdk5/GSKbeta signaling cascade has a potential role as a target for neurodegenerative diseases related to aging.

Hemodynamic steroid responsiveness is predictive of neurological outcome after traumatic brain injury.

INTRODUCTION: To determine the impact of physiologic doses of hydrocortisone on neurologic outcome after traumatic brain injury (TBI). METHODS: We conducted a retrospective study in a neurocritical care unit at a university teaching hospital. We included 29 patients with moderate and severe TBI requiring vasoactive drugs to maintain adequate arterial blood pressure who received corticosteroid. Infected patients were excluded. Blood cortisol levels were measured before and 30 and 60 minutes after the administration of a high-dose corticotropin stimulation test (HDST). Patients received hydrocortisone replacement therapy (200-300 mg/day) and vasoactive drugs requirements were noted. Intracranial pressure was managed according to a predefined protocol. RESULTS: A total of 14 out of 29 (48%) of patients were classified as responders to hydrocortisone (stopping vasoactive drugs within 3 days of starting hydrocortisone). The Glasgow Outcome Score (GOS) was used to assess neurologic outcome at 6 months. A favorable outcome (GOS 4 and 5) was observed in 11 out of 14 (79%) of responders and five out of 15 (33%) of nonresponders (p = 0.03). Of the responders, 12 out of 14 (85%) had a baseline cortisol below 414 nmol/L, and five out of 14 (36%) had primary adrenal insufficiency (AI) (primary AI: low baseline cortisol, and poor response to the HDST). Age, severity of injury, and response to hydrocortisone were predictive of outcome in multiple logistic regression analysis. CONCLUSIONS: Adrenal insufficiency is frequent after TBI, and hydrocortisone replacement therapy seems to be associated with a favorable neurologic outcome.

Effects of the dopaminergic agent and NMDA receptor antagonist amantadine on cognitive function, cerebral glucose metabolism and D2 receptor availability in chronic traumatic brain injury: a study using positron emission tomography (PET).

PRIMARY OBJECTIVE: This study was performed to assess effects of amantadine (AMH), a dopaminergic agent and NMDA antagonist, on chronic traumatic brain injury (TBI). The primary hypotheses were that amantadine treatment would result in executive function improvement and increased activity in pre-frontal cortex. RESEARCH DESIGN: An open-label design was used. METHODS: Twenty-two subjects underwent neuropsychological testing pre- and post-12 week treatment. Six subjects also underwent PET scanning. INTERVENTION: Amantadine 400 mg was administered per day. RESULTS: Significant improvements on tests of executive function were observed with treatment. Analysis of PET data demonstrated a significant increase in left pre-frontal cortex glucose metabolism. There was a significant positive correlation between executive domain scores and left pre-frontal glucose metabolism. CONCLUSIONS: This is the first known study to assess amantadine in chronic TBI using PET and the data are consistent with the hypotheses. The conduction of further studies is warranted.

A preliminary study of the efficacy of ondansetron in the treatment of ataxia, poor balance and incoordination from brain injury.

BACKGROUND: Ataxia is caused by a variety of conditions leading to imbalance, incoordination and other disabilities. Current treatment is largely symptomatic. Ondansetron (a 5-HT3 antagonist) has been established as an anti-emetic in cancer patients, but has recently been shown to improve vertigo and cerebellar tremor in some patients. HYPOTHESIS: Ondansetron can improve symptoms of ataxia, imbalance and incoordination in four brain-injured patients. DESIGN: Placebo-controlled, double blind, crossover, 'n of 1' study, A-B-A design. SUBJECTS: Four patients with ataxia from traumatic brain injury. METHODS: Four patients underwent five separate tests of ataxia under three different conditions in a double blind fashion. RESULTS: For all subjects, there was little difference in scores in the five areas tested, with some improvement in tests of lower limb ataxia (10.4% for 4 mg and 10.7% for 8 mg ondansetron vs baseline). CONCLUSION: Ondansetron use showed a trend towards improvement in tests of lower extremity ataxia but did not consistently improve scores in four patients.

Orally disintegrating olanzapine for the treatment of psychotic and behavioral disturbances associated with dementia.

Orally disintegrating olanzapine is a recently marketed form of olanzapine that dissolves rapidly on contact with saliva. We describe six demented patients resistant to treatment with common oral antipsychotic medications who were successfully treated with the formulation. The importance of these case reports is to make physicians aware that orally disintegrating olanzapine may be useful for the management of psychobehavioral disturbances in demented patients who resist or have difficulty taking standard oral medications.

A review of cholinergic agents in the treatment of neurobehavioral deficits following traumatic brain injury.

Although traumatic brain injury (TBI) frequently results in significant handicap, empirical investigations of pharmacological treatment of the neurobehavioral sequelae of TBI are rare. This review presents evidence that supports hypotheses of a cholinergic mechanism underlying some neurobehavioral sequelae of TBI, as well as a critical review of the preliminary evidence supporting the efficacy of cholinergic agents in TBI. Despite numerous methodological limitations, preliminary evidence exists for the efficacy of cholinergic agents in ameliorating attention and memory deficits following TBI. The authors highlight the need for large, randomized, double-blind, placebo-controlled trials that include a broad range of cognitive and behavioral outcome measures.

[Compulsive-obsessive disorder after severe head trauma: diagnosis and treatment]. / Zwangsstörung nach Schädel-Hirn-Trauma: Diagnostik und Therapie.

An 18-year-old man suffered a severe head trauma from a car accident. Eight months later the patient had a good general state of health. But at this time he was referred to our psychiatric hospital and he reported increased checking compulsions and aggressive obsessions. In addition there was increased impulsivity. The patient was treated with an selective-serotonin-reuptake-inhibitor (SSRI) and showed a clinical response. Obsessive-compulsive disorder (OCD) has rarely been described after traumatic brain injury. Clinical symptoms, neuropsychological dysfunctions, brain imaging and therapy are illustrated. The represented connections of the frontal brain lesions and OCD-symptoms with interventions in the serotonin system support the neurobiological hypotheses of the obsessive-compulsive disorder.

Pharmacological approach to functional reorganization: the role of norepinephrine.

Pharmacological studies in laboratory animals show that systemically administered drugs that modulate the levels of specific central neurotransmitters can influence post brain injury behavioral recovery. Several lines of evidence support an important role of central norepinephrine. Selective lesions of central noradrenergic pathways impair recovery after a subsequent injury to the cerebral cortex. Drugs that deplete central norepinephrine, block alpha 1-adrenergic receptors, or decrease norepinephrine release (alpha 2-adrenergic receptor agonists) impede recovery whereas drugs that increase norepinephrine release (alpha 2-adrenergic receptor antagonists) or sympathomimetics (amphetamine) facilitate recovery. These studies also provide insights into the potential neurobiological processes underlying these drug effects.

The effect of riluzole and mannitol on cerebral oedema after cryogenic injury in the mouse.

A cryogenic lesion was produced under halothane anaesthesia in the mouse by placing a cotton swab soaked in liquid nitrogen onto the surface of the cranium. This provoked an oedematous lesion which developed within the hour after the insult and evolved over the following week. Treatment with mannitol at 3 g/kg i.v. caused a significant 22% reduction in oedema 1 h later, when administered immediately after lesion, but not when administered 23-h post lesion. Likewise riluzole (16 mg/kg, i.v.) significantly reduced oedema by 17% when administered immediately after lesion, or 13% (P < 0.05) when administered 23 h after lesion. Repeated doses (2 x 16 mg/kg, i.p.) of riluzole were also able to reduce oedema significantly (24%, P < 0.05) at 24 h post lesion. Riluzole, in four repeated doses of 8 mg/kg i.p. was also able to reduce lesion surface size by 16% (P < 0.05) 48 h after lesion.

Treatment with amantadine potentiated motor learning in a patient with traumatic brain injury of 15 years' duration.

This study sought to determine whether pharmacotherapy with amantadine potentiates motor recovery in an 18-year-old man with traumatic brain injury (TBI) of 15 years' duration. This uncontrolled single-case multiple-baseline design allowed preliminary evaluation of amantadine within the context of standard data-collection procedures on the TBI unit. Measurements tracked speed of wheelchair propulsion, wheelchair transfer, donning shirt, and inserting pegs into holes. Data were collected during a 3-week practice period, followed by a 6-week period of practice plus daily treatment with amantadine. The rate at which performance improved was significantly increased with drug treatment in the wheelchair transfer task. There was a statistically insignificant trend toward improvement in donning shirt. Amantadine did not appear to potentiate recovery in the wheelchair propulsion or peg placement tasks. The results suggest that amantadine facilitates some measures of motor recovery in chronic brain injury. Further trials are warranted to investigate this issue.

Tratamento da insuficiência cerebral crônica com nicergolina / Treatment of chronic cerebral insufficiency with nicergoline

Em um esquema aberto, näo comparativo, 30 pacientes portadores de insuficiência cerebral crônica (ICC) foram tratados com nicergolina (Sermion) drágeas de 10 mg, na posologia de uma drágea três vezes ao dia por 12 semanas. As variaçöes observadas em relaçäo aos dados basais foram significativas para os sintomas clínicos e psicoafetivos avaliados (Teste dos Sinais unilateral). A eficácia foi considerada excelente ou boa em 28 (93,3%) pacientes e regular em dois (6,7%): A exceçäo de cinco pacientes que apresentaram cefaléia ocasional durante o tratamento, näo foram observados efeitos colaterais