The link between neurodegeneration and oxidative stress (regardless of its origin, mitochondria, arachidonic acid metabolism, nitric oxide synthase, xanthine oxidase (XO), NOX, etc.) is a long-debated topic and the involvement of reactive species in these pathologies is generally accepted. A question that derives from the previous topic is whether ROS are at the origin of neurodegeneration, the generated reactive species are responsible for disease progression, or both. Moreover, glutamate-induced neurotoxicity is not only limited to the presence of Ca²⁺ and the activation of caspases, but also through the inhibition of the cystine/glutamate antiport (x_c⁻), with the consequent decrease in GSH and the accumulation of ROS [129]. CBD reduces the degree of ROS-mediated neurotoxic damage in the cortical region, regardless of its origin, whether it is generated by N-methyl-D-aspartate (NMDA) receptors, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or kainate, which suggests either an inhibitory action on these receptors or an action on downstream proteins [112]. At the same time, previous studies have suggested and even stated that CBD has an antioxidant capacity similar to BHT, and in addition, it does not promote protumor effects, thus making it one of the most promising agents in this regard [83]. For example, in Parkinson’s disease (PD), the region affected by ROS is considered to be the substantia nigra pars compacta (SNpc), where the highest density of dopaminergic neurons is found, where the basal level of ROS is higher than in other areas of the brain, as a result of the intense metabolism of dopamine. Thus, these neurons are susceptible to the presence of oxidative stress, the decrease in their number causing the appearance of motor, but also cognitive, memory, and learning symptoms [99]. Thus, the addition of CBD in therapy increases the number of unaffected dopaminergic neurons, also suggesting the importance of the HO-1 system in neuroprotection [123]. At the same time, the continuous administration of CBD in preclinical studies led to the observation of decreased levels of MDA at the cortical and striatal level, as well as increased activity of antioxidant mechanisms in other areas (cortex and striatum) [130]. Similar effects could also be observed in various preclinical models of PD [131,132].

The presence of neuroinflammation within controlled limits is imperative for the restoration of neuronal tissue, but such a particular state continues to be associated with the development of neurodegenerative diseases [133]. Without a well-known mechanism, the density of CB2 receptors in microglia increases under oxidative stress conditions, as seen in multiple sclerosis, AD, and PD. The activation of these receptors causes the inhibition of microglia activity, hence the reduction in neuronal toxicity mediated by ROS and RNS [134,135], by decreasing glial fibrillary acidic protein expression (GFAP) [136]. At the same time, CB2 activation improves blood–brain barrier (BBB) function and reduces inducible nitric oxide synthase (iNOS) expression as a result of extracellular signal-regulated kinase 1/2 inhibition (ERK 1/2) [137]. It is suggested that CBD exerts its neuroprotective and antioxidant properties in a unique manner that is independent of CB2, TRPV1, or PPARγ receptors. In experimental studies aimed at testing the effect of CBD in AD, it reduced iNOS activity, decreased tau protein hyperphosphorylation, MDA levels, and caspase 3 activity [138]. In the case of Huntington’s disease, 3-nitropropionic acid (3-NP) is used to generate a model as close as possible to the pathology. The administration of CBD led to the rescue of neurons, independent of CB2 receptors, the most likely reason being the antioxidant effect [139].

Other mechanisms involved in the control of inflammation are the inhibition of NF-κB and also of the genes that encode the expression of molecules with a pro-inflammatory role (iNOS, COX2, cytokines, and metalloproteinases) [140]. Additionally, the inhibitory control of NF-κB can be achieved by reducing the phosphorylation of kinases involved in the transcription of this factor such as p38 mitogen-activated protein kinase (p38 MAPK) [137]. Additionally, in the same category of mechanisms with neuroprotective potential are included 5-HT_1A receptors, adenosine reuptake inhibition, and the WNT/β-catenin signaling pathway, which has an important role in β-amyloid (Aβ)-induced glycogen synthase kinase-3 beta activation (GSK-3β) and tau hyperphosphorylation [141,142].

Several studies have focused on investigating how CBD works in neurodegenerative diseases. Thus, in animal models (rats) of AD, CBD treatment prevented cognitive impairments and reduced the risk of progression via PPARγ and SOD. It is also not excluded that AEA, whose level increases in the presence of CBD, and reduces the formation of β-amyloid, as suggested in cell culture studies, also has an important role. As previously stated, other studies also support the inhibition of the GSK-3β protein complex through TRPV1-mediated phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) activation and protection of neuronal plasticity by reducing ROS and inflammation [143,144,145,146].

Literature reports suggest that the accumulation of Aβ destabilizes the redox balance, generates massive amounts of ROS (promotes lipid peroxidation reactions, protein, and DNA oxidation) [147], and stimulates pro-inflammatory reactions, which ultimately result in disease progression [148]. On the same note, NF-κB, a factor sensitive to changes in oxidative homeostasis, which is activated by the family of stress-activated protein kinases (SAPKs), which includes p38 MAPK, regulates the transcription of pro-inflammatory factors and the immune response, but also induces iNOS in neurons affected by the presence of Aβ, both in cell cultures and in post-mortem studies on the brains of AD patients [149,150,151]. Thus, it is demonstrated that CBD exerts an inhibitory effect on both NF-κB and p38 MAPK, ultimately determining the reduction in iNOS expression with the limitation of the disruptive effects of oxidative stress, and at the same time being responsible for the protection of PC12 cells from the negative effect of Aβ [137]. The idea is strengthened by the fact that CBD protects PC12 neurons in an antioxidant manner and also reduces the hyperphosphorylation of tau proteins through the WNT/β-catenin pathway [112], diminishing the inflammatory markers generated by Aβ, such as GFAP and IL-1β, these effects being the sum of complex and dynamic processes [152,153,154,155]. Another cause of the vicious circle created by ROS and the progression of Aβ plaque aggregation (which generates in vitro, H₂O₂, and ${\mathrm{O}}_2^{-}$), is the presence of increased concentrations of transition metal ions (Cu²⁺, Fe³⁺) in the brain of patients (postmortem) diagnosed with AD [156,157,158]. In this sense, the chelating properties of CBD, along with the antioxidant ones, can constitute an alternative treatment [159].

In the case of cell cultures (PC12 cell line), treated with MPP⁺, the inclusion of CBD under these conditions resulted in increased viability of these cells and also the expression of the axonal protein, Growth Associated Protein 43 (GAP-43). CBD also stimulates neurite formation but, in a manner, is closely related to the tropomyosin kinase A receptor (TrkA) and not to the nerve growth factor (NGF) [157]. Depending on the time of administration, i.e., the time elapsed since the injury occurred, CBD has the ability to restore the dopamine level, as demonstrated in the case of the injection of 6-hydroxydopamine (6-OHDA), and is proposed as a mechanism, the activation of the antioxidant systems and CB2 receptors, respectively, TRPV1 expressed at nigrostriatal level, as well as COX2 inhibition [132].

Preclinical models based on 3-NP induce striatal toxicity, but apparently, CBD can increase gamma-aminobutyric acid (GABA) levels and protect GABAergic neuron projections in the SN, increase BDNF, reduce ROS, and also reduce cellular signaling via the PI3K/Akt pathway, independent of CB2 or TRPV1 receptors, whereas the reduction in iNOS is mediated by CB2 [102,139,160,161,162]. It is very likely that in this case too, the beneficial effects of CBD are mediated through the Nrf2/ARE pathway, as it is known that in the case of 3-NP intoxication, the expression of Nrf2 is increased [163,164,165].

An important aspect to specify is that oxidative stress is not only found in neurodegenerative conditions but also in particular psychiatric conditions. Thus, regarding ROS, it doesn’t need to constitute the origin of these conditions, but rather the aggravation of symptoms and brain functions. In this sense, mental states characterized by stress induce ROS by altering the balance of excitatory neurotransmitters (adrenaline, glutamate), serotonin, and GABA, which also modulate the immune response and maintain the body’s homeostasis and the functionality of the hypothalamic-pituitary-adrenal axis (HPA) [166]. For this purpose, in post-traumatic stress syndrome (PTSD), CBD finds applicability by blocking FAAH and increasing available AEA [167,168,169]; in depression, CBD alleviates symptoms by stimulating serotoninergic neurotransmission, mediated by 5-HT_1A, and by activating the BDNF-TrkB complex [170,171,172], whereas in anxiety and fear, these beneficial effects are mediated by the same 5-HT_1A receptor, but also by GABA_A receptors, respectively, by inhibiting the enzymatic activity of iNOS and FAAH [173].

These positive effects exerted by CBD (antioxidant, neuroprotective) have also been investigated outside the context of neurodegenerative diseases. Thus, in the case of toxicity mediated by alcohol consumption (in the rat binge alcohol model), CBD limited the pathological changes in the hippocampal region, the proposed mechanism is based on antagonizing the effect of glutamate, beyond the stimulation of NMDA receptors (by glutamate), being demonstrated neuronal decline by alcohol, through the influence on mitochondria, resulting in ROS [174]. Additionally, in a cardiotoxicity model using doxorubicin, CBD limited this effect by enhancing mitochondrial complex I activity and also GPx activity [175]. The same antioxidant behavior of CBD could also be observed in a cisplatin-induced nephrotoxicity model [124].

Another area of interest in the use of CBD is the effect of this compound on the skin. Thus, it is known that ultraviolet radiations (UV), UVA, and UVB produce a redox imbalance, which results in the degradation of the normal structure of the skin with possible consequences such as photoaging and photocarcinogenesis [176,177]. Apparently, at this level as well (keratinocytes), CBD can induce Nrf2 and decrease ROS. In addition, an increase in the level of thioredoxin and the activity of thioredoxin reductase is observed, a system through which the activity of apoptosis-regulating kinase (ASK-1) is inhibited, thus protecting cells from apoptosis induced by ROS and irradiation [178,179,180,181]. Moreover, CBD reduces the signaling of apoptotic pathways by restoring Ca²⁺ homeostasis at the mitochondrial level [166]. Under physiological conditions, CBD activates A₂ receptors with a reduction in NF-κB activity and a consequent decrease in TNF-α [182,183]. Another proposed mechanism is that through which CBD stimulates the formation of an anti-inflammatory prostaglandin, 15d-PGJ2, which regulates COX activity and also the redox balance by facilitating the dissociation of Nrf2 from Keap1, an effect that promotes HO-1 transcription and finally the rescue of irradiated keratinocytes [184,185,186,187]. Related to Nrf2, it seems that continuous and prolonged activation of this factor increases the risk of malignancies and creates an environment favorable to the development, proliferation, and creation of resistance to chemotherapy and radiotherapy through antioxidant mechanisms [188,189] At the same time, it is suggested that CBD reduces the transcription of Nrf2, manifesting in this way the protection of cells [190].

In addition to influencing Nrf2 and HO-1, various studies state that CBD has an inhibitory effect on BTB Domain and CNC Homolog 1 (BACH1), a transcription factor involved in ROS generation [90,121,188,191,192,193]. This BACH1 can be considered as a functional antagonist of Nrf2, in the absence of oxidative stress, by binding to Maf recognition elements (MAREs), regions indispensable for the coding of genes with an antioxidant role, following that the same Nrf2 will restore the levels of BACH1, decreased due to oxidative stress [194] (see Figure 2). Other studies claim that, in fact, in keratinocytes, CBD is a weak activator of Nrf2 and rather a strong inhibitor of BACH1 [193].