Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities

Abstract

The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population. Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy. Chronic epilepsy is typified by spontaneous recurrent seizures, cognitive dysfunction, and depression, which are associated with persistent inflammation, significantly waned neurogenesis, and abnormal synaptic reorganization. Thus, alternative approaches that are efficient not only for curtailing SE-induced initial brain injury, neuroinflammation, aberrant neurogenesis, and abnormal synaptic reorganization but also for thwarting or restraining the progression of SE into a chronic epileptic state are needed. In this review, we confer the promise of cannabidiol, an active ingredient of Cannabis sativa, for preventing or easing SE-induced neurodegeneration, neuroinflammation, cognitive and mood impairments, and the spontaneous recurrent seizures.

Introduction

A neurological condition displaying self-enduring, continuous tonic-clonic seizure lasting ≥ 5 min or a cluster of seizures occurring close together with no recovery between seizures for ≥ 30 min is called status epilepticus (SE) [1]. SE is a severe neurologic ailment. Unremitting seizures can initiate extensive brain damage with functional deficits as well as death in some cases, if not interrupted with a combination of antiepileptic drugs (AEDs) [1–4]. Multiple neurological conditions including brain trauma, brain infections, brain tumor, febrile seizures, stroke, congenital malformations, Alzheimer’s disease, sleep deprivation, abrupt discontinuation of AED in a seizure-prone individual, alcohol, or street drugs can cause SE. The prevalence of SE varies from 10 to 61 cases per 100,000 individuals in a year, with a mortality rate of ~ 20% [1, 5, 6]. However, higher incidences of SE are seen in children and the elderly.

Many clinical and preclinical studies in the last decade have focused on understanding the causes, pathophysiology, prognosis, treatment, and enduring complications of SE [7, 8]. While SE can cause injury to multiple regions of the brain, the hippocampus is one of the most sensitive areas of the brain to SE-induced adverse long-term alterations. The early phase after SE displays multiple changes. These include neurodegeneration, increased oxidative stress, inflammation, and increased and abnormal neurogenesis in the hippocampus [9–14]. This phase may continue for days or weeks, following which multiple epileptogenic changes progress for variable periods [15]. For instance, the abnormal migration of newly born neurons continues into the dentate hilus, which can further enhance abnormal circuitry formation [16–20]. On the other hand, the dentate granule cell axons (mossy fibers) sprout into the inner molecular layer and the CA3 stratum oriens and form abnormal synapses, which can increase hyperexcitability of neurons [21–25]. Moreover, a progressive loss of GABA-ergic interneurons and alterations in GABA receptors can decrease inhibitory neurotransmission [26–29]. Changes in other neurotransmitters and their receptors can also alter the excitation-inhibition balance in neurotransmission [30–32]. Furthermore, astrocytes display structural and functional alterations [33], and elevated oxidative stress and inflammatory conditions endure [34–36]. Additionally, neurogenesis and multiple neurotrophic factor levels wane considerably [16]. Dispersion of granule cell layer may also occur [37]. Thus, multiple changes likely contribute to hippocampal hyperexcitability and cognitive and mood impairments after SE.

All epileptogenic changes mentioned above may not occur in every case of SE. The extent of alterations varies considerably with the intensity, duration, and type of SE. Nonetheless, an episode of SE can lead to chronic temporal lobe epilepsy (TLE) characterized by spontaneous recurrent seizures (SRS) and cognitive and mood impairments as comorbidities [38–41]. The occurrence of TLE after SE may take months, years, or even decades, as it depends on the extent and the speed by which the various epileptogenic alterations reach certain thresholds to tilt excitation-inhibition homeostasis into a state of hyperexcitability. While most cases of TLE can be controlled through the intake of a single or combination of AEDs, over 30% of TLE cases are drug-resistant. Lack of seizure control may lead to continued neurodegeneration, inflammation, severe cognitive deficits, and mood dysfunction. Considering these, effective therapies that not only terminate SE but also thwart and substantially restrain epileptogenic changes occurring after SE are needed. Conventional antiepileptic drug therapy is effective for ending or significantly reducing seizures in most cases [7]. However, AEDs have not shown significant efficacy for preventing or reducing SE-induced epileptogenesis and cognitive and mood impairments. From this perspective, alternative drugs, natural compounds, cells, or cell products that can suppress oxidative stress and neuroinflammation provide neuroprotection and maintain neurogenesis to near normal levels after SE has received significant attention. In this review, we focus on discussing the promise of a natural product cannabidiol for easing SE-induced neuroinflammation, epileptogenesis, chronic seizures, and related comorbidities.

Source of Cannabidiol and Historical Background

The use of Cannabis sativa in religious rituals and for recreation has been documented since millenniums. Medicinal formulations of C. sativa have also been used since ancient times for treating multiple conditions. These include menstrual sickness, gout, fever, glaucoma, nausea, muscle spasms, anxiety, Alzheimer’s disease, Huntington’s disease, neuropathic pain, headache, and epilepsy [42–46]. Nonetheless, the use of C. sativa for treating disease conditions is uncommon in the modern age due to ethical and cultural notions about the psychostimulant effect of Δ9-tetrahydrocannabinol (Δ9-THC), one of the active ingredients of C. sativa. However, a fact that was overlooked for long is the presence of hundreds of C21 terpenophenolic compounds, distinguished as phytocannabinoids in C. sativa. These include cannabidiol (CBD), cannabichromene, and cannabigerol, all of which are nonpsychoactive compounds with several medicinal functions [47–49].

Effects of Cannabidiol on Spontaneous Seizures in Epilepsy Patients and Animal Models

Although the two principal components of C. sativa (THC and CBD) showed efficacy for preventing seizures as well as reducing mortality in an animal model of SE with low toxicity and high tolerability [39], CBD received much attention by the scientific community because of its nonpsychostimulant property. Many studies have demonstrated that the hippocampus and the adjacent brain areas contain high levels of CBD receptors (CB1 receptors), which are G-protein-coupled receptors regulating several brain functions [50–52]. For example, these receptors can regulate calcium influx into neurons during hyperexcitability, a characteristic feature of epilepsy [53]. Indeed, CBD has antiepileptiform and anticonvulsant effects in in vitro and in vivo models of epilepsy [54–62]. CBD can also ameliorate social deficits [60, 61]. Besides, CBD can mediate neuroprotective effects in models of hypoxic-ischemic and self-sustained seizures [62, 63].

There have been many reports on the efficacy of cannabis extracts or CBD for controlling seizures in children with epilepsy. These reports are based mostly on surveys, where parents reported the beneficial effects of oral cannabis extracts enriched with CBD in their children afflicted with some form of refractory epilepsy. These include Dravet syndrome (severe myoclonic epilepsy of infancy), Doose syndrome (myoclonic astatic epilepsy), infantile spasms, Lennox-Gastaut syndrome, West syndrome, Ohtahara syndrome, and idiopathic generalized epilepsy. Porter and Jacobson reported that 84% of 19 children with refractory epilepsy who used an average of 12 AEDs earlier displayed reduced frequency of seizures with cannabidiol-enriched cannabis [64]. Hussain and colleagues report a survey that comprised 117 children with epilepsy receiving CBD-enriched cannabis preparations following failed seizure reduction for 5 years with eight AEDs. The median duration of CBD treatment was 6.8 months, and the median dosage was 4.3 mg/kg/day. Interestingly, 85% of children displayed reduced seizure frequency with 14% showing no seizures [65]. Another survey comprised 75 patients that included both children and adolescents with epilepsy [66]. Seizure control was observed in 57% of patients with 33% displaying over 50% reduction in the frequency of seizures. There were also improvements in behavior and alertness (33%), language (10%), and motor skills (10%). However, adverse events were seen in 44% of patients with 13% exhibiting an enhanced frequency of seizures and 12% showing somnolence or fatigue [66]. A survey by Tzadok and associates reports varying levels of seizure reduction in 89% and aggravated seizures in 7% of children with epilepsy [67]. Several recently published surveys also report similar findings in children and adults with refractory epilepsy. These include decreased frequency of seizures in (i) ~ 81% of children (n = 43) [68], (ii) ~ 90% of adults and ~ 71% of children [69], and (iii) 49% in children and adolescents [70]. Some side effects were also seen in ~ 42% of patients, however [68]. These surveys, while interesting, raise issues such as participation bias, lack of blinded outcome analyses, and the accuracy of seizure numbers. The epilepsy patients, parents of patients, and most medical professionals seem to believe that the available evidence on safety and efficacy is sufficient for employing CBD in treating epilepsy [71]. However, majority of epileptologists like to have additional proof about the safety and efficacy of CBD prior to its widespread clinical use [71].

Indeed, the anticonvulsant property of CBD in humans is also evident from some clinical trials (Fig. 1). A first open-label study by Devinsky and colleagues showed the efficacy of CBD in epileptic patients for reducing motor seizures with acceptable toxicity and tolerability [72]. A study by Hess and associates showed the tolerability of CBD as well as its efficacy to reduce the frequency of seizures by ~ 48% in 50% of tuberous sclerosis patients displaying refractory seizures [73]. In another study involving five subjects with Sturge-Weber syndrome, CBD treatment for over a year was well tolerated with milder side effects and induced 50% reduction in seizures [74]. Importantly, a recent randomized, double-blind, placebo-controlled clinical trial performed by Devinsky and colleagues showed the effectiveness of CBD in treating drug-resistant seizures in children afflicted with the Dravet syndrome [75]. In patients receiving CBD treatment at 20 mg/kg/day, the median seizure frequency was reduced from 12.4 to 5.9 seizures per month with 5% of patients reaching seizure-free status, in comparison to placebo-treated patients maintaining 14–15 seizures per month. CBD was well tolerated with reduced side effects than other approved AEDs [76, 77]. Another recent study by Warren and colleagues showed that pharmaceutical grade CBD (Epidiolex; Greenwich Biosciences) is efficacious for reducing seizure severity in three patients with brain tumor-related refractory epilepsy [78]. In addition to the clinical trials described above, there are individual case reports supporting the beneficial effects CBD for reducing seizures [79, 80].

Fig. 1.

Summary of clinical trials and animal studies reporting the efficacy of cannabidiol (CBD) as an anticonvulsant and/or antiepileptogenic agent (the upper half) and the potential mechanisms by which CBD provides seizure suppression and neuroprotection (the lower half). Clinical trials have demonstrated the efficacy of CBD to diminish seizure frequency in adult epilepsy patients as well as in children with Dravet syndrome or tuberous sclerosis (see the upper left region). Animal studies have shown the effectiveness of CBD therapy for modulating status epilepticus (SE) and/or SE-induced epilepsy using intrahippocampal pilocarpine, maximal electroshock, corneal kindling, and other acute seizure models (see the upper right region). The properties of CBD that promote seizure suppression include its ability to reduce intracellular calcium in neurons, inhibit the release of excitatory neurotransmitter glutamate, reduce the uptake and degradation of anandamide, and enhance adenosine levels (see the lower left region). The neuroprotective properties of CBD are supported by its ability to activate cannabinoid receptor signaling pathways; reduce oxidative stress, transforming growth factor-alpha (TNFa), interleukin-1 beta (IL-1b), and the associated inflammatory reaction; activate peroxisome-proliferator-activated receptor gamma (PPAR-gamma) signaling pathway; and inhibit nitric oxide (see the lower right region)

Epilepsy is also typified by several comorbidities which interfere with day to day life. These neuropsychiatric symptoms include cognitive and behavioral impairments such as anxiety, depression, and stress [81, 82]. It is of great importance to treat such symptoms in the early stages of life with epilepsy to improve the quality of life and to prevent any unnecessary social discomfort associated with epilepsy. In this context, it is worthy to note that pediatric epileptic patients receiving CBD showed significant improvements in quality of life measures such as energy versus fatigue, cognition, memory, and control versus helplessness [83]. In another study, Press and associates reported improved behavior, alertness, language, and motor skills in ~ 33% of 75 patients (children and adolescents) with refractory epilepsy after oral cannabis extract intake [66]. CBD also seem to promote anxiolytic activity, likely through facilitation of local 5-HT1A receptor-mediated neurotransmission [84].

Because of clinical evidence of anticonvulsant effects as well as several anecdotal cases reported by the media, many countries have approved CBD for the treatment of epilepsy, particularly with regularly employed AEDs not offering satisfactory seizure control. Thus, about controlling seizures in chronic epileptic conditions, CBD has already shown considerable promise. Seizure-suppressing feature of CBD makes this drug a promising candidate for the treatment of drug-resistant epilepsies. However, rigorous clinical studies such as double-blind, placebo-controlled larger trials are required in the future to establish CBD as a drug of choice for treating refractory epilepsy. Furthermore, side effects of CBD with long-term use for controlling seizures in chronic epilepsy is unknown, especially its effects on comorbidities of epilepsy such as cognitive impairments and depression. In this context, studying the various effects of long-term administration of CBD in animal models of chronic epilepsy is critically required.

Prospects of CBD for Easing SE and SE-Induced Epileptogenesis

The efficiency of CBD to modulate epileptogenesis after SE is still unclear. Only a few studies have investigated the efficacy of CBD administration for SE (Fig. 1). In a recent animal study, Do Val-da Silva and colleagues pretreated Wistar rats with intraperitoneal CBD an hour prior to inducing SE through an intrahippocampal microinjection of pilocarpine [63]. In this study, CBD pretreatment increased the latency to SE development, reduced the severity of SE from Racine scale 4 to Racine scale 3, and diminished neurodegeneration in the dentate hilus and CA3 subfield of the hippocampus. Moreover, CBD affected spontaneous local field potentials in the contralateral hippocampus during SE by increasing the latency to epileptiform discharges and reducing powers in delta and theta oscillations. This study provided the baseline data to demonstrate the potential of CBD for reducing neurodegeneration and related changes. However, pretreatment approach has little translational value since CBD is not taken as a daily dietary supplement.

Recently, the National Institute of Neurological Disorders and Stroke funded Epilepsy Therapy Screening Program has examined the effectiveness of intraperitoneal CBD treatment in mouse 6 Hz 44 mA, maximal electroshock (MES), and corneal kindling models, and in a rat MES prototype [85]. In these studies, CBD pretreatment provided dose-dependent protection in acute seizure models as well as in the chronic corneal kindled mice. Furthermore, a recent open-label clinical study in children afflicted with febrile infection-related epilepsy syndrome (an epileptic encephalopathy) showed that CBD significantly reduced seizures that are typically resistant to AED, immune modulatory, and dietary therapies [86]. Importantly, CBD treatment in the subacute or chronic phase led to not only reduction in seizure frequencies but also improvements in motor, cognitive, and verbal function [86]. Collectively, the above studies suggest the potential of CBD for easing SE or SE-induced epileptogenesis. However, detailed long-term studies in several SE models will be required for making definite conclusions on the efficacy of CBD for mitigating SE-induced epileptogenesis. Furthermore, rigorous safety studies in SE models utilizing postnatal, young, adult, and aged rodents examining the different doses of CBD on maximal tolerance, somatic and metabolic changes, motor and sensory function, cognition, and mood function are required. Besides, the efficacy of CBD needs to be tested with commonly used benzodiazepine drugs or other AEDs that terminate SE or prevent the occurrence of SRS in the early phase after SE to understand drug-drug interactions and the possible additive beneficial or adverse effects. These issues are important because CBD can alter the concentration of other drugs [87, 88].

Potential Mechanisms by Which CBD Modulates Seizures and Epileptogenesis

The mechanisms by which CBD exerts seizure-suppressing and neuroprotective effects are unknown. It is plausible that the beneficial effects of CBD are mediated through the activation of the cannabinoid receptor signaling in the brain because activation of endocannabinoid system can control the excitability of neurons [89]. Precisely, brief postsynaptic depolarization during neurotransmission can trigger the release of endocannabinoids such as N-arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG) synthesized from postsynaptic membrane phospholipid precursors in response to increased intracellular calcium [90, 91]. The anticonvulsant activity of CBD possibly involves inhibition of the cellular uptake and catabolism of anandamide, which can increase the concentration of endocannabinoids [92, 93]. These endocannabinoids can bind to G-protein-coupled CB1 receptors in presynaptic terminals to reduce the neurotransmitter release [89]. These phenomena have been elegantly demonstrated in excitatory axons synapsing on Purkinje cells of the cerebellum as “depolarization-induced suppression of excitation.” Similar events in inhibitory axons synapsing on pyramidal neurons of the hippocampus are known as “depolarization-induced suppression of inhibition” [89, 94, 95].

Thus, the endocannabinoids act as synaptic circuit breakers by binding to CB1 receptors [96–98]. CB1 receptors are found on axon terminals in multiple brain regions [97, 99, 100]. These include the various areas of the neocortex, hippocampus, amygdala, basal ganglia, thalamus, hypothalamus, nucleus accumbens, substantia nigra, ventral tegmental area, cerebellum, and brain stem [89, 96]. From this perspective, exogenous compounds or drugs that can act on CB1 receptors in excitatory axon terminals may be particularly useful for controlling hyperexcitability of neurons in conditions such as SE or chronic epilepsy. However, it is unlikely that the effect of CBD on seizure suppression is solely due to CB1 receptor signaling because CBD has low affinity for CB1 receptors [101, 102]. CBD is likely suppressing seizures through several mechanisms. These may comprise its ability to reduce the intracellular calcium [53, 89], diminish the release of glutamate, and antagonize G protein-coupled receptor 55, a counterpart of the canonical CB1 receptor signaling pathway [103]. Antiseizure effects of CBD may also occur through modulation of potassium ion channels as well as voltage-gated sodium channels [104, 105]. The blockade of sodium channels by CBD may not directly correlate with anticonvulsant effects [106] but may involve activation and desensitization of transient receptor potential vanilloid 1 (TRPV1) channels to reduce hyperexcitability [107]. Alternative mechanisms of CBD action include its ability to hinder the uptake of adenosine, an endogenous anticonvulsant [108, 109], and inhibit the uptake and degradation of anandamide, an endocannabinoid [92, 110].

CBD may restrain epileptogenesis after SE through several mechanisms. For example, CBD can suppress oxidative stress by acting as a potent antioxidant agent and thereby provide neuroprotective effects through CB1 receptor-independent mechanism [111–113]. Furthermore, CBD can modulate inflammation through suppression of tumor necrosis factor-alpha, a potent pro-inflammatory cytokine contributing to neuroinflammation after SE [111, 114–116]. These antiinflammatory effects need particular attention because neuroinflammation contributes to epileptogenesis after SE, stroke, Alzheimer’s disease, and traumatic brain injury, and the occurrence of seizures in chronic epilepsy [117–123]. Moreover, through activation of mTOR pathway, CBD can reduce glutamate release and diminish seizure activity [124]. Additional mechanisms such as activation of peroxisome proliferator-activated receptor-gamma and inhibition of the release of nitric oxide and interleukin-1 beta may also be involved [125]. Thus, it is plausible that CBD eases epileptogenesis and related comorbidities after SE through multi-pronged actions described above.

Conclusions and Future Studies

CBD has promise for inhibiting SE and SE-induced epileptogenic modifications through antiseizure and antiepileptogenic effects, based on studies in animal models and its efficacy for reducing seizures in patients with refractory epilepsy. However, a recent case report using CBD whole plant extract (cannabidiol oil) failed to show beneficial effects in a patient with super refractory status epilepticus [126]. Considering these, detailed studies on CBD treatment in distinct animal models of SE are urgently needed to fully understand its efficacy as an effective neuroprotective and antiepileptogenic drug. These may encompass CBD treatment initiating at different time points after SE for comparing the effectiveness of early intervention versus delayed intervention stratagems. Additionally, studying CBD treatment continuing for variable durations after SE in immediate, latent, and chronic phases after SE will be critical to recognize its effects on diverse facets of epileptogenesis and its proficiency to block chronic epilepsy development after SE-induced brain injury. Likewise, the underlying mechanisms by which CBD curbs epileptogenic changes need to be investigated in more detail.