6.4. Effects Of Endocannabinoids And Related Compounds On Neurodegenerative Diseases Part 4

Not only inflammatory disorders or tissue injury but also neurodegenerative diseases are accompanied or caused by neuroinflammation. Neurodegeneration also refers to chronic and progressive loss of brain and spinal cord neuronal functions. 

Inflammation is a self-protection mechanism of the body that helps us fight off pathogens when our bodies are injured or infected while promoting tissue repair. However, excessive or long-term inflammation has negative effects on physical health, including memory loss.

Early studies have shown a link between inflammation and Alzheimer's disease, while some recent studies have shown that inflammation may have a more extensive impact on memory. This is because inflammation affects the signaling between neurons and the survival of neurons, leading to memory loss.

However, not all types of inflammation hurt memory. Some studies have found that inflammation against the intestinal bacterial flora may lead to memory loss, while inflammation against infectious or autoimmune diseases does not necessarily affect memory. In addition, inflammation will only hurt memory when it is long-term or chronic, so long-term stress and unhealthy lifestyles should be avoided.

Fortunately, we can reduce the risk of chronic inflammation by making lifestyle changes. For example, maintaining a healthy diet, getting enough sleep, exercising, and reducing stress can help control inflammation and maintain good memory. In addition, doctors may recommend some medications to control inflammation, such as nonsteroidal anti-inflammatory drugs and steroid hormones.

In conclusion, although inflammation may hurt memory, we can maintain good memory by controlling inflammation through a healthy lifestyle and necessary medical intervention. We should face challenges positively and maintain a positive attitude to keep our bodies and brains healthy. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from its various active ingredients, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in many ways.

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Particularly, AD is characterized by amyloid β plaques and neurofibrillary tangles that cause a decline in memory and cognitive abilities. In addition to neuroinflammation, systemic infection, and inflammation, characterized by a substantial amount of proinflammatory mediators in the circulation, have also been correlated to increased risks of developing AD [195]. 

Chronic inflammation is also a hallmark of PD, which is characterized by the loss of dopaminergic neurons and the presence of α-synuclein-containing aggregates in the substantia nigra pars compacta [196]. 

Huntington's disease (HD) is a devastating neurodegenerative genetic disorder associated with progressive loss of a specific type of neurons found in the striatum and cortex [197]. 

Unfortunately, the relationship between neuroinflammation markers and the disease pathology is still poorly understood [198]. Amyotrophic lateral sclerosis (ALS) is indicated by the degeneration of motor neurons [199] and is characterized by the occurrence of a neuroinflammatory reaction consisting of activated glial cells, mainly microglia astrocytes, and T cells [200]. 

Of the neurodegenerative diseases, multiple sclerosis (MS) is an exception because neuronal death in MS is considered to be secondary to the initiating activity of autoreactive T cells that target myelin [201]. 

While neuroinflammation in MS involves infiltration of peripheral immune cells, breakdown of the BBB, and activation of CNS-resident glial cells, neuroinflammation in other neurodegenerative diseases is more restricted to glial cell activation and inflammatory reactions in the parenchyma [201].

Several animal models and human studies have demonstrated that the ECS significantly influences the development of neuroinflammation and the progression of brain injury and neurodegenerative diseases [1–3]. 

Using a model of cerebral focal ischemia, it was shown that exogenously administered AEA and 2-AG in combination reduced infarct size in rats, but with no facilitatory effects beyond AEA or 2-AG alone [202]. 

Other studies reported neuroprotective effects of exogenous AEA [203] and 2-AG [56] under traumatic brain injury (TBI). Several studies documented the positive effects of PEA in experimental and clinical studies of TBI, spinal cord injuries, pain, cerebral ischemia, PD, and AD [179–181,183–185,204–208]. Moreover, the stimulation of CB1 and CB2 is beneficial in neurodegenerative disorders such as AD and PD (reviewed in [209,210]). 

In contrast, the CB1 inverse agonist SR141716A (rimonabant) showed promising results in PD preclinical studies [211,212]; however, clinical studies with SR141716A failed to improve motor disability in PD patients [213]. 

Importantly, SR141716A, which has also been approved as an effective anti-obesity drug, shows a serious psychiatric side effect profile and thus has been withdrawn from the pharmaceutical market worldwide. 

These contradictory data, indicate the interference of CB1 inverse agonists/antagonists with a basal ECS tone, prevailing in healthy conditions and essentially involved in the homeostatic regulation of brain function. It has been observed that CB2 receptors and FAAH are selectively overexpressed in neuritic plaque-associated glia in AD [214], especially in reactive astrocytes and activated microglial cells [215]. 

In this regard, the use of hydrolase inhibitors has been mentioned as a promising therapeutic option for neuroinflammatory and neurodegenerative diseases. 

Treatment with MAGL and FAAH inhibitors, which can increase the level of eCBs indirectly, leads to anxiolytic, antidepressant, and anti-inflammatory effects, and reduces amyloid β deposition and inhibition of the death of dopaminergic neurons, which are associated with the pathogenesis of AD and PD, respectively (reviewed in [216,217]). 

An overview of in vivo studies reviewing the effects of MAGL and FAAH inhibitors in neuroinflammation and neurodegenerative diseases, is given in Table 3. Several FAAH and MAGL inhibitors entered clinical phase I and II studies for neurological disorders such as pain, anxiety, Tourette syndrome, and cannabis withdrawal. 

Moreover, dual FAAH/cholinesterase inhibitors which might be beneficial for neurodegenerative diseases are currently under development [218]. In addition, an increasing number of studies have characterized the beneficial effects of NA inhibitors, which prevent the degradation of NAEs, in preclinical studies of pain and (neuro-) inflammation [219–221] (Table 3). 

However, in a phase I study, the FAAH inhibitor BIA 10-2474 resulted in severe adverse events such as lethal toxic cerebral syndrome [222], leading to the discontinuation of several clinical studies employing FAAH inhibitors. Thus, there is an urgent need for further research to develop highly specific, short-acting, indirect cannabinoid therapies with better safety profiles.

7. The Role of the Blood–Brain Barrier Integrity in Restriction of Systemic Inflammation

CNS dysfunction associated with systemic infection is common and includes symptoms such as sickness behavior and delirium. In the context of sepsis, CNS dysfunction is known as septic encephalopathy. A key step in the pathogenesis is the systemic production of pro-inflammatory cytokines such as TNF-α and IL-1β, which then act on the brain. Cytokine transport systems of the BBB are likely to play a role in permitting the passage of these signals [241]. 

Moreover, AD, MS, and CNS dysfunction in systemic infection are examples of conditions that are primarily neurodegenerative, neuroinflammatory, or systemic. 

In many cases, it is not clear whether BBB changes are the cause or consequence of neuropathology, and BBB changes and neuropathology may drive each other in a self-perpetuating manner, contributing to disease progression.

7.1. Structure of the Blood-Brain Barrier

Histologically the BBB is a specialized multi-layered unit composed of a thick continuous glycocalyx, non-fenestrated endothelial cells with reduced vesicular activity and linked by tight junctions, two basement membranes (vascular basement membrane and glia limitans), and astrocytic end-feet. All elements of this 'neurovascular unit' contribute to the functional BBB. 

At the molecular level, there are ectoenzymes, receptors, and transporters that regulate or reverse traffic across the BBB. Together, these components enable a stable CNS environment to minimize the traffic of inflammatory cells and molecules, local inflammation, and prevent potential neuronal damage.

7.2. The BBB in Systemic Inflammation

Systemic inflammation, as induced by LPS, can lead to disruptive and non-disruptive BBB changes. Disruptive BBB change is accompanied by endothelial cell damage or tight junctional modifications, while non-disruptive change occurs at a molecular level. 

Identified mechanisms of LPS-induced disruptive BBB change include modification of tight junctions, endothelial damage and apoptosis, degradation of glycocalyx, breakdown of glia limitans, and astrocyte alteration (reviewed in [242]). 

Moreover, several reports demonstrate that systemic inflammation upregulates several endothelial cell receptors and transporters, induces cytokine production by endothelial cells, modulates astrocyte function, and enhances pathogen neuroinvasion without any visible changes in the BBB architecture [242].

7.3. The Role of the ECS in the Maintenance of the Blood Brain Barrier

2-AG is the most abundant endocannabinoid in the CNS and is elevated after brain injury and during neuroinflammation. Because of its rapid hydrolysis, however, the compensatory and neuroprotective effect of 2-AG is short-term. It has been shown previously that 2-AG decreases BBB permeability and inhibits the acute expression of the main proinflammatory cytokines TNF-α, IL-1β, and IL-6 [243]. 

Moreover, several reports demonstrated that inhibition of 2-AG and AEA degradation supports the BBB integrity in experimental traumatic brain injury [244,245] and ischemic insults [175]. 

Accordingly, CB2 agonists prevent BBB damage in several experimental models of brain injury and neurodegenerative disease [188,246–257]. Previously, Hind and colleagues suggested that AEA, OEA, and PEA may play an important modulatory role in normal BBB physiology, and afford protection to the BBB during ischemic stroke [258]. 

In addition, it has been shown that PPAR-α is involved in the protective effects of OEA and OEA analogs against ischemic brain injury, particularly in terms of BBB disruption [259,260]. 

A study from Mestre and colleagues suggested that CB1 receptor-dependent inhibition of vascular cell adhesion molecule (VCAM) 1 is a novel mechanism for AEA-induced leukocyte transmigration through the BBB [261]. 

Moreover, CB1 receptor blockade reduced leukocyte adhesion to intestinal microvasculature in a mouse model of systemic sepsis [213], potentially also affecting immune cell transmigration at the BBB. The major endogenously produced NAE and one of the most stable among these compounds, SEA prevents leukocyte, especially neutrophil, infiltration into the brain in a murine model of LPS-induced systemic inflammation [47].

7.4. Leukocyte Recruitment

Leukocytes entering the brain from peripheral circulation must pass through the BBB, the choroid plexus that forms the blood-cerebrospinal fluid barrier, and through post-capillary venules at the pial surface into subarachnoid and Virchow-Robin perivascular spaces [262,263].
These routes typically operate together and both the paracellular (junctional) and transcellular (non-junctional) mechanisms can be involved in leukocyte trafficking across the neurovascular unit [264]. 

Although cellular influx into the CNS is physiologically non-disruptive, it may result in disruptive BBB change. Leukocyte recruitment across the BBB in response to systemic inflammation has been demonstrated for lymphocytes [265], neutrophils [266], and monocytes [267]. Mechanistically, systemic inflammation can promote leukocyte transmigration at various points during the two-step passage through the endothelium and glial limitans. On circulatory immune cells, CB1 and CB2 receptors are expressed at low levels in healthy human donors. 

The highest expression levels of CB2 were observed in NK cells, B-cells, and monocytes, while low levels could be found in T cells and neutrophils isolated from the peripheral blood of healthy donors [268]. Stimulation with pro-inflammatory cytokines, such as IL-6 and TNF-α, enhanced the transcription of both CB receptors, while the effect was more pronounced for CB2 [269]. 

In line with this, pro-inflammatory cytokine stimulation of murine bone marrow-derived macrophages increased CB2 expression [270], rendering inflammatory macrophages more susceptible to CB signaling. A detailed overview of the reported effects of CB1 and CB2 receptor activation in leukocytes is given in Table 4.

8. Conclusions

Neuroinflammation is caused and/or accompanied by the infiltration of immune cells through the BBB and secretion of a range of pro-inflammatory cytokines and other molecules with neurotoxic potential. 

These changes together with glutamate receptor-mediated neurotoxicity and neurodegenerative processes underlie the pathogenesis of several neuropathologies, among them are Alzheimer's disease, amyotrophic lateral sclerosis, stroke, multiple sclerosis, and Parkinson's disease. Bacterial and viral infection, traumatic injury, and autoimmune disease compromise the integrity of BBB and favor the transition of systemic inflammation to neuroinflammation. 

Maintenance or restoration of the selective permeability of the blood-brain barrier is one of the therapeutic strategies under systemic inflammation to prevent systemic inflammation from spreading to the CNS. 

The interplay of true eCB and ligands that now belong to expanded ECS allows for taking into consideration all relevant molecular targets for the therapy of neuroinflammation-associated neuropathologies. The interference of eCB congeners with enzymatic degradation or endocannabinoid signaling suggests their role in tuning the activity of primary eCBs. 

The 'entourage effect' of the produced non-cannabinoid 2-acylglycerols, NAEs, and N-acyl neurotransmitters may serve as an additional fine regulator of cannabinoid activity. Resident microglia and astrocytes are tightly coupled to functions of active synaptic contacts and are highly involved in inflammatory progression, pro-survival changes, and resolution of neuroinflammation. 

These cells promote neuronal survival, synaptogenesis, spine induction, and illumination and protect neurons from toxic metabolites. The contribution of eCB signaling to the functional coupling of neurons, astrocytes, and microglia, suggests that in line with the conception of tripartite synapses, microglial cells are equal participants in such communication. 

Being activated during the immune response, microglial cells contribute to the resolution of neuroinflammation; however, chronic activation of microglia is detrimental to neurons and contributes to the development of synaptopathy in various neurodegenerative diseases. Components of ECS play an active role in the reactivity of these cells during inflammation, attenuate the production of pro-inflammatory cytokines, and mediate neuroprotection against glutamate-receptor-mediated excitotoxicity, ischemia, and oxidative stress. 

Normal synaptic activity as well as pathological overstimulation of postsynaptic neurotransmitter receptors is a potent trigger for the production of eCBs and non-cannabinoid NAEs. Glutamate-induced endocannabinoids [78] flown from active synapses and injured sites might attract resident microglial cells [76,79]. 

Tight structural and functional cooperation of synaptic contacts, astrocytes, and microglia enables highly dynamic responses to synaptic events. Retrograde endocannabinoid signaling is implicated in several forms of short- and long-term synaptic plasticity. These lipid mediators reach the presynaptic sites of the same or other synaptic contacts and by binding to CB1/2 inhibit the synaptic vesicle fusion and neurotransmitter release. 

This is how synaptic contacts dynamically tune their strength and can potentiate/depress the response depending on present inputs. Released eCBs have a restricted area of action due to short half-lives and differences in CB receptor expression on cells in close vicinity. Thus, the concentration gradient of eCBs is formed on the site of their synthesis. 

This makes the pharmacological inhibition of eCB degradation primarily effective in injured sites, where they are actively produced. Novel, highly selective inhibitors of FAAH and MAGL with a good safety profile may become prospective agents with anti-nociceptive, anxiolytic, and anti-inflammatory activity and targeted action. 

The overall interplay and metabolism of endogenous ligands of CB1/2, TRPV1, GPR55, and GPR18 are now integrated into the "endocannabinoidome", which is actively involved in the intrinsic response to inflammation and neuroinflammation. 

The polymodality of this system provides a wide field for the development of highly efficient neuroprotective agents for the therapy of inflammation-associated synaptopathy.

Author Contributions: Conceptualization, E.M.S. and L.A.K.; writing-original draft preparation, E.M.S., L.A.K., and S.R.; writing-review and editing, E.M.S., L.A.K., and S.R.; supervision, E.M.S. and L.A.K. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported by the Austrian Science Fund (FWF) grant W1241, the NIH grant R35 GM122567, and by the OeAD grant UA 09/2017.

Acknowledgments: Open Access Funding by the Austrian Science Fund (FWF). Figures were created with Biorender.com (accessed on 7 April 2021).

Conflicts of Interest: The authors declare no conflict of interest.

References

1. Basavarajappa, B.S.; Shivakumar, M.; Joshi, V.; Subbanna, S. Endocannabinoid system in neurodegenerative disorders. J. Neurochem. 2017, 142, 624–648. [CrossRef] [PubMed] 

2. Schurman, L.D.; Lichtman, A.H. Endocannabinoids: A Promising Impact for Traumatic Brain Injury. Front. Pharmacol. 2017, 8, 69. [CrossRef] [PubMed] 

3. Ranieri, R.; Laezza, C.; Bifulco, M.; Marasco, D.; Malfitano, A.M. Endocannabinoid System in Neurological Disorders. Recent Patents CNS Drug Discov. 2016, 10, 90–112. [CrossRef] [PubMed] 

4. Tsuboi, K.; Uyama, T.; Okamoto, Y.; Ueda, N. Endocannabinoids and related N-acyl ethanolamines: Biological activities and metabolism. Inflamm. Regen. 2018, 38, 28. [CrossRef] [PubMed] 

5. Bisogno, T.; Berrendero, F.; Ambrosino, G.; Cebeira, M.; Ramos, J.; Fernandez-Ruiz, J.; Di Marzo, V. Brain Regional Distribution of Endocannabinoids: Implications for Their Biosynthesis and Biological Function. Biochem. Biophys. Res. Commun. 1999, 256, 377–380. [CrossRef]

6. Felder, C.C.; Nielsen, A.; Briley, E.M.; Palkovits, M.; Priller, J.; Axelrod, J.; Nguyen, D.N.; Richardson, J.M.; Riggin, R.M.; Koppel, G.A.; et al. Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of humans and rats. FEBS Lett. 1996, 393, 231–235. [CrossRef] 

7. Schmid, H.H.; Schmid, P.C.; Berdyshev, E.V. Cell signaling by endocannabinoids and their congeners: Questions of selectivity and other challenges. Chem. Phys. Lipids 2002, 121, 111–134. [CrossRef] 

8. Natarajan, V.; Reddy, P.; Schmid, P.; Schmid, H. On the biosynthesis and metabolism of N-acylethanolamine phospholipids in infarcted dog heart. Biochim. Biophys. Acta BBA Lipids Lipid Metab. 1981, 664, 445–448. [CrossRef] 

9. Gulaya, N.M.; Volkov, G.L.; Klimashevsky, V.M.; Govseeva, N.N.; Melnik, A.A. Changes in lipid composition of neuro-blastoma C1300 N18 cell during differentiation. Neuroscience 1989, 30, 153–164. [CrossRef] 

10. Kasatkina, L.A.; Tarasenko, A.S.; Krupko, O.O.; Kuchmerovska, T.M.; Lisakovska, O.O.; Trikash, I.O. Vitamin D deficiency induces the excitation/inhibition brain imbalance and the proinflammatory shift. Int. J. Biochem. Cell Biol. 2020, 119, 105665. [CrossRef] 

11. Murataeva, N.; Straiker, A.; Mackie, K. Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS. Br. J. Pharmacol. 2014, 171, 1379–1391. [CrossRef] 

12. Kozak, K.; Marnett, L. Oxidative metabolism of endocannabinoids. Prostaglandins Leukot. Essent. Fat. Acids 2002, 66, 211–220. [CrossRef] [PubMed]

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