cannabidiol and Brain-Injuries--Traumatic

A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple sclerosis (MS), stroke and traumatic brain injury (TBI), which are three of the most prevalent demyelinating disorders. Thanks to the properties described for CBD and its interesting profile in humans, both the phytocannabinoid and derivatives could be considered as potential candidates for clinical use. In this review we will summarize current advances in the use of CBD and other cannabinoids as future potential treatments. While new research is accelerating the process for the generation of novel drug candidates and identification of druggable targets, the collaboration of key players such as basic researchers, clinicians and pharmaceutical companies is required to bring novel therapies to the patients.

Topics: Brain Injuries, Traumatic; Cannabidiol; Cannabinoids; Cannabis; Demyelinating Diseases; Humans; Multiple Sclerosis; Stroke

To assess the efficacy, safety, and tolerability of oromucosal nabiximols cannabinoid medicine as adjunct therapy for children with spasticity due to cerebral palsy/traumatic central nervous system injury with inadequate response to existing treatment.. Overall, 72 patients (mean [SD] age 12y 4mo [3y 1mo], range 8-18y) were randomized at a ratio of 2:1 to receive nabiximols (n=47; 29 males, 18 females) or placebo (n=25; 15 males, 10 females) for 12 weeks (12 sprays/day max. based on clinical response/tolerability). The primary outcome was change from baseline in level of spasticity on a 0 to 10 Numerical Rating Scale (NRS), assessed by the primary caregiver at 12 weeks. Secondary outcomes included additional measures for spasticity, sleep quality, pain, health-related quality of life, comfort, depression, and safety.. There was no significant difference in the spasticity 0 to 10 NRS between nabiximols versus placebo groups after 12 weeks. No statistically significant differences were observed for any secondary endpoint. Adverse events were predominantly mild or moderate in severity; however, three cases of hallucinations were reported.. Nabiximols was generally well tolerated; however, neuropsychiatric adverse events were observed. No significant reduction in spasticity with nabiximols treatment versus placebo was observed.. Oromucosal nabiximols is generally well tolerated by paediatric patients. However, three cases of hallucinations were observed, one of which involved auditory hallucinations and a suicide attempt. Oromucosal nabiximols versus placebo did not reduce cerebral palsy/central nervous system injury-related spasticity.. Evaluar la eficacia, seguridad y tolerabilidad del cannabinoides nabiximol de aplicación en spray bucal como terapia complementaria para niños con espasticidad debido a parálisis cerebral o lesión traumática del sistema nervioso central que no responden al tratamiento convencional. MÉTODO: En total, 72 pacientes (media [DE] edad 12 años 4 meses [3 años 1 mes], rango 8-18 años) fueron aleatorizados en una proporción de 2: 1 para recibir nabiximol spray (n = 47; 29 masculinos, 18 femeninos) o placebo (n = 25; 15 masculinos, 10 femeninos) durante 12 semanas (12 aplicaciones de spray / día máx basados en la respuesta clínica / tolerabilidad). El resultado primario fue el cambio en el nivel basal de espasticidad en una Escala de Calificación Numérica (NRS) de 0 a 10, evaluada por el cuidador primario a las 12 semanas. Los resultados secundarios incluyeron medidas adicionales para la espasticidad, la calidad del sueño, el dolor, la calidad de vida relacionada con la salud, el confort, la depresión y la seguridad.. No hubo diferencias significativas en la espasticidad de 0 a 10 NRS entre los grupos de que recibieron nabiximol versus el grupo placebo después de 12 semanas. No se observaron diferencias estadísticamente significativas para ningún criterio de valoración secundario. Los eventos adversos fueron predominantemente leves o moderados en severidad; sin embargo, se informaron tres casos de alucinaciones. INTERPRETACIÓN: El nabiximol fue generalmente bien tolerado; sin embargo, se observaron eventos adversos neuropsiquiátricos. No se observó una reducción significativa en la espasticidad con el tratamiento con nabiximoles versus placebo.. Avaliar a eficácia, segurança e tolerabilidade do medicamento oromucosal nabiximols canabinóide como terapia adjunta para crianças com espasticidade devida a paralisia cerebral/lesão traumática do sistema nervoso central com resposta inadequada a tratamentos existentes. MÉTODO: Em geral, 72 pacientes (média [DP] idade 12a 4m [3a 1m], variação 8-18a) foram randomizados em uma taxa de 2:1 para receber nabiximols (n=47; 29 sexo masculino, 18 sexo feminino) ou placebo (n=25; 15 sexo masculino, 10 sexo feminino) por 12 semanas (12 sprays/dia máx. com base na resposta clínica/tolerabilidade). O resultado primário foi mudança com relação a linha de base no nível de espasticidade um uma Escala Numérica de Pontuação (ENP) de 0 a 10, avaliada pelo cuidador primário com 12 semanas. Resultados secundários incluíram medidas adicionais de espasticidade, qualidade do sono, dor, qualidade de vida relacionada à saúde, conforto, depressão, e segurança.. Não houve diferença significativa na espasticidade Segundo a ENP 0 a 10 entre os grupos nabiximols versus placebo após 12 semanas. Nenhuma diferença estatisticamente significativa foi observada para nenhum desfecho secundário. Eventos adversos foram predominantemente leves ou moderados em severidade; no entanto, três casos de alucinações foram reportados. INTERPRETAÇÃO: Nabiximols foi em geral bem tolerado; no entanto eventos adversos neuropsiquiátricos foram observados. Nenhuma redução significativa na espasticidade com o tratamento com nabiximols versus placebo foi observada.

Topics: Administration, Oral; Adolescent; Brain Injuries, Traumatic; Cannabidiol; Cerebral Palsy; Child; Double-Blind Method; Dronabinol; Drug Combinations; Female; Humans; Male; Muscle Spasticity; Treatment Outcome

Traumatic brain injury (TBI) is characterized by a primary mechanical injury and a secondary injury associated with neuroinflammation, blood-brain barrier (BBB) disruption and neurodegeneration. We have developed a novel cannabidiol aminoquinone derivative, VCE-004.8, which is a dual PPARγ/CB. Using a phosphoproteomic approach, we investigated the effects of VCE-004.8 on prolyl hydroxylase domain-containing protein 2 (PHD2) posttranslational modifications. The potential role of PP2A/B55α in HIF activation was analyzed using siRNA for B55α. To evaluate the angiogenic response to the treatment with VCE-004.8 we performed a Matrigel plug in vivo assay. Transendothelial electrical resistance (TEER) as well as vascular cell adhesion molecule 1 (VCAM), and zonula occludens 1 (ZO-1) tight junction protein expression were studied in brain microvascular endothelial cells. The efficacy of VCE-004.8 in vivo was evaluated in a controlled cortical impact (CCI) murine model of TBI.. Herein we provide evidence that VCE-004.8 inhibits PHD2 Ser125 phosphorylation and activates HIF through a PP2A/B55α pathway. VCE-004.8 induces angiogenesis in vivo increasing the formation of functional vessel (CD31/α-SMA) and prevents in vitro blood-brain barrier (BBB) disruption ameliorating the loss of ZO-1 expression under proinflammatory conditions. In CCI model VCE-004.8 treatment ameliorates early motor deficits after TBI and attenuates cerebral edema preserving BBB integrity. Histopathological analysis revealed that VCE-004.8 treatment induces neovascularization in pericontusional area and prevented immune cell infiltration to the brain parenchyma. In addition, VCE-004.8 attenuates neuroinflammation and reduces neuronal death and apoptosis in the damaged area.. This study provides new insight about the mechanism of action of VCE-004.8 regulating the PP2A/B55α/PHD2/HIF pathway. Furthermore, we show the potential efficacy for TBI treatment by preventing BBB disruption, enhancing angiogenesis, and ameliorating neuroinflammation and neurodegeneration after brain injury.

Topics: Animals; Blood-Brain Barrier; Brain Injuries, Traumatic; Cannabidiol; Disease Models, Animal; Endothelial Cells; Mice; Neovascularization, Pathologic

Despite the high incidence of traumatic brain injury (TBI), there is no universal treatment to safely treat patients. Blunt brain injuries destroy primary neural tissue that results in impaired perfusion, excessive release of glutamate, inflammation, excitotoxicity, and progressive secondary neuronal cell death. We hypothesized that administration of cannabidiol (CBD) directly to a brain contusion site, will optimize delivery to the injured tissue which will reduce local neural excitation and inflammation to spare neural tissue and improve neurological outcome following TBI. CBD was infused into a gelfoam matrix forming an implant (CBDi), then applied over the dura at the contusion site as well as delivered systemically by injection (CBD.IP). Post-injury administration of CBDi+IP greatly reduced defecation scores, lesion volume, the loss of neurons in the ipsilateral hippocampus, the number of injured neurons of the contralateral hippocampus, and reversed TBI-induced glial fibrillary acidic protein (GFAP) upregulation which was superior to either CBD.IP or CBDi treatment alone. Vestibulomotor performance on the beam-balance test was restored by 12 days post-TBI and sustained through 28 days. CBDi+IP treated rats exhibited preinjury levels of spontaneous alternation on the spontaneous alternation T-maze. In the object recognition test, they had greater mobility and exploration of novel objects compared to contusion or implant alone consistent with reduced anxiety and restored cognitive function. These results suggest that dual therapy by targeting the site of injury internally with a CBD-infused medical carrier followed by systemic supplementation may offer a more effective countermeasure than systemic or implant treatment alone for the deleterious effects of penetrating head wounds.

Topics: Animals; Brain Injuries, Traumatic; Cannabidiol; Cognition; Female; Male; Maze Learning; Patient Acuity; Postural Balance; Rats; Rats, Sprague-Dawley; Rats, Wistar; Recognition, Psychology

Topics: Brain Injuries, Traumatic; Cannabidiol; Cannabinoids; Cerebral Palsy; Child; Dronabinol; Drug Combinations; Humans; Medicine; Muscle Spasticity; Safety