This study aimed to determine if orally administered cannabidiol (CBD) lessens the cortical over-release of glutamate induced by a severe traumatic brain injury (TBI) and facilitates functional recovery. The short-term experiment focused on identifying the optimal oral pretreatment of CBD. Male Wistar rats were pretreated with oral administration of CBD (50, 100, or 200 mg/kg) daily for 7 days. Then, extracellular glutamate concentration was estimated by cortical microdialysis before and immediately after a severe TBI. The long-term experiment focused on evaluating the effect of the optimal treatment of CBD (pre- vs. pre- and post-TBI) 30 days after trauma. Sensorimotor function, body weight, and mortality rate were evaluated. In the short term, TBI induced a high release of glutamate (738% ± 173%; p < 0.001 vs. basal). Oral pretreatment with CBD at all doses tested reduced glutamate concentration but with higher potency at when animals received 100 mg/kg (222 ± 33%, p < 0.01 vs. TBI), an effect associated with a lower mortality rate (22%, p < 0.001 vs. TBI). In the long-term experiment, the TBI group showed a high glutamate concentration (149% p < 0.01 vs. SHAM). In contrast, animals receiving the optimal treatment of CBD (pre- and pre/post-TBI) showed glutamate concentrations like the SHAM group (p > 0.05). This effect was associated with high sensorimotor function improvement. CBD pretreatment, but not pre-/post-treatment, induced a higher body weight gain (39% ± 2.7%, p < 0.01 vs. TBI) and lower mortality rate (22%, p < 0.01 vs. TBI). These results support that orally administered CBD reduces short- and long-term TBI-induced excitotoxicity and facilitated functional recovery. Indeed, pretreatment with CBD was sufficient to lessen the adverse sequelae of TBI.

Traumatic brain injury (TBI) represents a critical public health problem around the world. To date, there are no accurate therapeutic approaches for the management of cardiovascular impairments induce by TBI. In this regard, hydrogen sulfide (H ₂ S), a novel gasotransmitter, has been proposed as a neuro- and cardioprotective molecule. This study was designed to determine the effect of subchronic management with sodium hydrosulfide (NaHS) on hemodynamic, vasopressor sympathetic outflow and sensorimotor alterations produced by TBI. Animals underwent a lateral fluid percussion injury, and changes in hemodynamic variables were measured by pletismographic methods. In addition, vasopressor sympathetic outflow was assessed by a pithed rat model. Last, sensorimotor impairments were evaluated by neuroscore test and beam-walking test. At seven, 14, 21, and 28 days after moderate-severe TBI, the animals showed: (1) a decrease on sensorimotor function in the neuroscore test and beam-walking test; (2) an increase in heart rate, systolic, diastolic, and mean blood pressure; (3) progressive sympathetic hyperactivity; and (4) a decrease in vasopressor responses induced by noradrenaline (α _1/2 -adrenoceptors agonist) and UK 14,304 (selective α ₂ -adrenoceptor agonist). Interestingly, intraperitoneal daily injections of NaHS, an H ₂ S donor (3.1 and 5.6 mg/kg), during seven days after TBI prevented the development of the impairments in hemodynamic variables, which were similar to those obtained in sham animals. Moreover, NaHS treatment prevented the sympathetic hyperactivity and decreased noradrenaline-induced vasopressor responses. No effects on sensorimotor dysfunction were observed, however. Taken together, our results suggest that H ₂ S ameliorates the hemodynamic and sympathetic system impairments observed after TBI.

Drug-resistant epilepsy (DRE) is associated with high extracellular levels of glutamate. Studies support the idea that cannabidiol (CBD) decreases glutamate over-release. This study focused on investigating whether CBD reduces the evoked glutamate release in cortical synaptic terminals obtained from patients with DRE as well as in a preclinical model of epilepsy. Synaptic terminals (synaptosomes) were obtained from the epileptic neocortex of patients with drug-resistant temporal lobe epilepsy (DR-TLE, n = 10) or drug-resistant extratemporal lobe epilepsy (DR-ETLE, n = 10) submitted to epilepsy surgery. Synaptosomes highly purified by Percoll-sucrose density gradient were characterized by confocal microscopy and Western blot. Synaptosomes were used to estimate the high KCl (33 mM)-evoked glutamate release in the presence of CBD at different concentrations. Our results revealed responsive tissue obtained from seven patients with DR-TLE and seven patients with DR-ETLE. Responsive tissue showed lower glutamate release (p < 0.05) when incubated with CBD at low concentrations (less than 100 µM) but not at higher concentrations. Tissue that was non-responsive to CBD (DR-TLE, n = 3 and DR-ELTE, n = 3) showed high glutamate release despite CBD exposure at different concentrations. Simultaneously, a block of the human epileptic neocortex was used to determine its viability through whole-cell and extracellular electrophysiological recordings. The electrophysiological evaluations supported that the responsive and non-responsive human epileptic neocortices used in the present study exhibited proper neuronal viability and stability to acquire electrophysiological responses. We also investigated whether the subchronic administration of CBD could reduce glutamate over-release in a preclinical model of temporal lobe epilepsy. Administration of CBD (200 mg/kg, p.o. every 24 h for 7 days) to rats with lithium-pilocarpine-evoked spontaneous recurrent seizures reduced glutamate over-release in the hippocampus. The present study revealed that acute exposure to low concentrations of CBD can reduce the glutamate over-release in synaptic terminals obtained from some patients with DRE. This effect is also evident when applied subchronically in rats with spontaneous recurrent seizures. An important finding was the identification of a group of patients that were non-responsive to CBD effects. Future studies are essential to identify biomarkers of responsiveness to CBD to control DRE.

Severe traumatic brain injury (TBI) results in significant functional disturbances in the hippocampus. Studies support that sodium cromoglycate (CG) induces neuroprotective effects. This study focused on investigating the effects of post-TBI subchronic administration of CG on hippocampal hyperexcitability and damage as well as on sensorimotor impairment in rats. In contrast to the control group (Sham+SS group), animals undergoing severe TBI (TBI+SS group) showed sensorimotor dysfunction over the experimental post-TBI period (day 2, 55%, p < 0.001; day 23, 39.5%, p < 0.001; day 30, 38.6%, p < 0.01). On day 30 post-TBI, TBI+SS group showed neuronal hyperexcitability (63.3%, p < 0.01). The hippocampus ipsilateral to the injury showed volume reduction (14.4%, p < 0.001) with a volume of damage of 0.15 ± 0.09 mm ³ . These changes were associated with neuronal loss in the dentate gyrus (ipsilateral, 33%, p < 0.05); hilus (ipsilateral, 77%, p < 0.001; contralateral, 51%, p < 0.001); Cornu Ammonis (CA)1 (ipsilateral, 40%, p < 0.01), and CA3 (ipsilateral, 52%, p < 0.001; contralateral, 34%, p < 0.01). Animals receiving subchronic treatment with CG (50 mg/kg, s.c. daily for 10 days) after TBI (TBI+CG group) displayed a sensorimotor dysfunction less evident than that of the TBI+SS group ( p < 0.001). Their hippocampal excitability was similar to that of the Sham+SS group ( p = 0.21). The TBI+CG group presented hippocampal volume reduction (12.7%, p = 0.94) and damage (0.10 ± 0.03 mm ³ , p > 0.99) similar to the TBI+SS group. However, their hippocampal neuronal preservation was similar to that of the Sham+SS group. These results indicate that CG represents an appropriate and novel pharmacological strategy to reduce the long-term sensorimotor impairment and hippocampal damage and hyperexcitability that result as consequences of severe TBI.