Cannabidiol Reduces Short- and Long-Term High Glutamate Release after Severe Traumatic Brain Injury and Improves Functional Recovery

Abstract

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.

Cannabidiol's neuroprotective properties and potential treatment of traumatic brain injuries

“…Current studies of CBD's effects on TBI suggest that CBD dosing and achieved concentrations are critical for achieving therapeutic benefits [e.g., ( 56 )]. Other characteristics such as method of administration [e.g., ( 13 )], duration of exposure, and temporal proximity to the TBI [e.g., ( 12 )] further complicate efforts for achieving a clear understanding of optimal therapeutic strategies.…”

“…Addressing the time course of CBD's efficacy will be a critical experimental consideration moving forward. There is currently insufficient evidence to draw any definitive conclusions because in many cases, CBD is administered prior to the primary injury [e.g., ( 12 )], after [e.g., ( 13 )], or both before and after [e.g., ( 56 )], and often not compared across administration period. Pretreatment may lead to lower mortality rates and improved sensorimotor function ( 12 ), but targeting at least some of CBD's mechanisms, like the ECS, within a “window of opportunity” of at least 15 min following the primary injury may also confer substantial neuroprotective benefits ( 124 ).…”

“…There is currently insufficient evidence to draw any definitive conclusions because in many cases, CBD is administered prior to the primary injury [e.g., ( 12 )], after [e.g., ( 13 )], or both before and after [e.g., ( 56 )], and often not compared across administration period. Pretreatment may lead to lower mortality rates and improved sensorimotor function ( 12 ), but targeting at least some of CBD's mechanisms, like the ECS, within a “window of opportunity” of at least 15 min following the primary injury may also confer substantial neuroprotective benefits ( 124 ). Given that the window of opportunity for CBD administration is not clearly defined or consistently tested, we discuss the following neuroprotective effects across a range of administration methods and temporal relationships to the primary injury.…”

“…Pre-clinical models suggest that CBD may normalize the glutamatergic and GABAergic signaling imbalance following TBI. CBD administered prior to TBI reduced the increase in cortical glutamate release ( 12 ). This benefit was maintained with continued CBD administration for at least 30 days post-TBI.…”

Cannabidiol treatment improves metabolic profile and decreases hypothalamic inflammation caused by maternal obesity

“…The treatment was administered 7 days a week for 3 weeks (Figure 1). Treatment dose and duration were chosen based on previous studies on different cognitive-assessment models with oral administration of CBD (41)(42)(43)(44)(45). Furthermore, we have performed a pilot study assessing doses of 2,5 mg/kg, 10 mg/kg, and 50 mg/kg, to which 50 mg/kg showed most significant positive results (data not shown).…”