Stroke remains the second most common cause of death and the third most common cause of disability worldwide. Approximately 80 % of strokes are attributable to the occlusion of a blood vessel (ischemic stroke), whilst the rest is mainly associated with vessel rupture (hemorrhagic stroke) [3]. When a blood vessel that irrigates the brain tissue is occluded, ischemic brain damage is triggered by excessive release of the excitatory neurotransmitter glutamate as a result of energy failure and ion gradient collapse, resulting in a reversal of glutamate uptake via glutamate transporters. Excessive glutamate-evoked Ca2+ entry via NMDA receptors further promotes cell death by triggering an excitotoxic cascade that involves the activation of Ca2+-dependent enzymes, the disruption of mitochondrial function, and cell necrosis or apoptosis. Ischemic brain injury is exacerbated by a robust inflammatory response that involves a local reaction, as well as an influx of blood-borne cells with production of inflammatory mediators, including cytokines, chemokines, proteases, reactive oxygen species, and vascular adhesion molecules (reviewed in [4]). For the acute phase of ischemic stroke, the only pharmacological treatment is the recanalization of the occluded vessel with thrombolytic therapy with tissue plasminogen activator. However, owing to its narrow time window, < 5 % of stroke patients receive this treatment. Although the use of mechanic thrombectomy is helping to expand this window, it is still imperative to pursue the search of new therapeutic targets amenable to pharmacological manipulation for stroke patients [5]. Traumatic brain injury (TBI) is another important focal form of acquired brain injury that occurs when a sudden trauma damages the brain. It is usually caused either by closed or by open, penetrating head injury, and is often the result of car accidents, firearms or falls [6]. Since its pathophysiology shares many of its mechanisms with stroke, we will address these 2 pathologies together. Both pathological conditions should be completed with the study of spinal injury, but owing to space constraints, we will not address the effects of cannabinoids in spinal injury here.

Cannabinoids have been proposed as promising neuroprotective agents for the treatment of stroke and TBI [7]. This possibility has been predominantly investigated in experimental models of both disorders in laboratory animals, although some of the studies supporting this promise have been conducted with the cannabinoid administered before the cytotoxic insults, a fact that is not possible to reproduce in the case of humans, so the results of these specific studies should be taken with the necessary caution. For stroke, most common models are those caused by middle cerebral artery occlusion (MCAO) in rats or mice, either permanent (pMCAO) or followed by reperfusion [transient MCAO (tMCAO)], as well as in vitro models of oxygen/glucose deprivation. In the case of TBI, damage is most commonly caused either by closed (concussion) or open head injury (stab wound). The cannabinoids having beneficial effects in these models included 1) dexanabinol (HU-211) [8–11], which is a synthetic compound having a chemical structure of a classic cannabinoid but no activity at cannabinoid receptors; 2) nonselective synthetic cannabinoid agonists such as HU-210, the active enantiomer of HU-211 [12], WIN 55,212-2 [13, 14], TAK-937 [15, 16], and BAY 38-7271 [17, 18]; 3) phytocannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) [19], which binds not only CB 1 R and CB 2 R, but also cannabidiol (CBD), which has no affinity at these receptors but was highly active against brain ischemia [20–22]; 4) endocannabinoids such as 2-arachidonoylglycerol (2-AG), in particular in TBI induced by closed head injury [23–25], but also in experimental ischemia [26], and also anandamide [27] and its related signaling lipids palmitoylethanolamide (PEA) [28], oleoylethanolamide [27], and N-arachidonoyl-L-serine (AraS) [29]; and 5) selective CB 2 R targeting ligands such as O-3853, O-1966, and JWH-133 [30–35]. Most of these studies were conducted with the cannabinoid administered at least after the cytotoxic insult [12–19, 21–26, 28–35]. In most cases, the benefits obtained with these cannabinoid-related compounds (e.g., improved neurological performance, reduced infarct size, edema, BBB disruption, inflammation and gliosis, and control of immunomodulatory responses) involved the activation of CB 1 R (e.g., HU-210 [12], WIN55,212-2 [13, 14], TAK-937 [15, 16], BAY 38-7271 [17, 18], Δ9-THC [19], and PEA [36]) and/or CB 2 R (e.g., AraS [29], O-3853, O-1966, and JWH-133 [30–35]) . Similar findings derive from experiments using mice with a genetic deficiency in CB 1 R or, to a lesser extent, CB 2 R. For example, CB 1 –/– mice showed increased infarct size and neurological deficits after tMCAO, concomitant with a reduction in cerebral blood flow and NMDA excitotoxicity [37], and a similar greater vulnerability was also found in TBI models [24], then supporting the protective role of CB 1 R against both pathological conditions. In the case of CB 2 –/– mice, results were controversial, with a study reporting larger cerebral infarction and a worsened neurological function after tMCAO [30], but others describing no differences using permanent MCAO [32, 33], despite the notable effects found in pharmacological experiments with compounds selectively activating the CB 2 R [30–35]. These types of agonists are particularly interesting for a possible therapeutic application in stroke and TBI because of the lack of psychoactivity of their selective agonists. In addition, their strong anti-inflammatory profile appears to be one of the most consistent mechanisms leading to reduction of the lesion, by actions affecting resident, vascular, and peripheral cells. It is also important to remark that the benefits of certain cannabinoids in acute stroke and TBI also involve effects on other pharmacological targets, such as the blockade of NMDA receptors (e.g., HU-211 [8–11]), the activation of 5-HT 1A receptors (e.g., CBD [20–22]), and the activation of transient receptor potential vanilloid-type 1 receptors (e.g., PEA [36] and AraS) [29]). It is also possible that part of these beneficial effects may be related to the hypothermic effects of cannabinoids, but it is well known that such effects are CB 1 R-mediated [12, 38, 39]. Lastly and apart from the acute phase, both stroke and TBI have in common a chronic phase characterized by severe functional sequelae. This late phase offers, at least theoretically, a broader window for promoting repair and decreasing disability, in which there might be some room for cannabinoids based on their capability to induce proliferation of neural progenitors cells [40, 41], their differentiation and migration at lesioned sites (Moro et al., unpublished results), or the differentiation of oligodendrocyte precursor cells to produce remyelination [42]—all these possibilities have already been investigated in experimental brain ischemia.

The neuroprotective and neurorepair effects of cannabinoids in stroke and TBI may be facilitated by the responses experienced by endocannabinoids and their receptors and enzymes during the progression of both pathological conditions. This may be the case, for example, of the transient accumulation of 2-AG at the site of injury in experimental TBI [23]. By contrast, in the neonatal rat brain, the exposure to concussive head trauma induced a moderate increase in the levels of anandamide and other N-acylethanolamines, but not of 2-AG and other 2-monoacylglycerols [43, 44]. Further studies demonstrated that these elevations are endogenous responses addressed to limit brain damage, as the inhibition of 2-AG and anandamide hydrolysis reduced brain damage and improved functional deficits in parallel to a reduction of proinflammatory responses in the mouse brain after TBI [45, 46]. Similar elevations of anandamide, 2-AG, and N-acylethanolamines have been detected in experimental cerebral ischemia [47–50]. As far as the cannabinoid receptors are concerned, most studies showed an upregulated expression of both CB 1 R and, in particular, CB 2 R in stroke, with neurons (for CB 1 R) and microglial/macrophages, astrocytes, and neutrophils (for CB 2 R) being the most common cellular substrates for these responses [33, 51–54]. However, some studies described downregulatory responses of both receptors at very early times after induction of ischemia [33, 55]. Upregulation of CB 2 R with no changes in CB 1 R have been found in TBI [56].