Submitted Successfully!
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Ver. Summary Created by Modification Content Size Created at Operation
1
Caterina Scuderi
 + 1652 word(s) 1652 2021-09-07 09:41:24 |
2 format corrected.
Beatrix Zheng
 + 410 word(s) 2062 2021-09-18 05:01:56 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Scuderi, C. Brain Aging in Pets. Encyclopedia. Available online: https://encyclopedia.pub/entry/14315 (accessed on 06 December 2023).
Scuderi C. Brain Aging in Pets. Encyclopedia. Available at: https://encyclopedia.pub/entry/14315. Accessed December 06, 2023.
Scuderi, Caterina. "Brain Aging in Pets" Encyclopedia, https://encyclopedia.pub/entry/14315 (accessed December 06, 2023).
Scuderi, C.(2021, September 17). Brain Aging in Pets. In Encyclopedia. https://encyclopedia.pub/entry/14315
Scuderi, Caterina. "Brain Aging in Pets." Encyclopedia. Web. 17 September, 2021.
Brain Aging in Pets
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ani11092584

Neuroinflammation is considered a highly preserved physiological defensive process, triggered by various insults that can reach the brain, aimed at restoring homeostasis. It allows the elimination of the underlying cause, repair injured tissue, and restore normal functions. However, under some circumstances, neuroinflammation can also have detrimental consequences.

aging cognitive dysfunction syndrome neuroinflammation neurodegeneration astrocyte microglia mast cells cat dog palmitoylethanolamide

1. Successful Aging and the Brain

Over the last decades, life expectancy is getting longer, and the traditional 65-year chronological age threshold for entering old age has recently been questioned in favor of the fixed remaining life expectancy as a better indicator [1]. Similarly, the life expectancy of dogs and cats has been increasingly expanding during the last years, mainly thanks to the tremendous improvement of veterinary nutrition and medicine [2][3][4]. Currently, dogs are considered senior when they enter the last 25% of their predicted life expectancy, while feline pets are viewed as “old” between 10 and 14 years, with geriatric age beginning thereafter [3].

In human medicine, successful aging is a multidimensional term to describe seniors with minimal physical and health impairment, autonomous and satisfactory social interactive life, as well as prompt cognitive function [5]. In veterinary medicine, “successfully aging” pets are considered those who do not show important impairments in daily routine [6] while usually manifesting slow deterioration in general activity and playing behavior [7]. Failure to respond to commands, decreased interest toward novelty, increased time spent sleeping, and frequency of phobias, as well as reduced ability to cope with mild social challenges are further features of normal aging in pets [8][9][10][11]. Learning and memory are not negatively affected in most cases, although cognitive abilities tend to slow down over time [12][13], especially if comorbidities are present, due to the recently acknowledged “frailty syndrome” of the elderly [14][15].

2. Neurobehavioral and Physical Signs

Age-related cognitive decline in pets is a hot topic in veterinary medicine, mainly due to its striking similarities with human Alzheimer’s disease (AD). Cognitive dysfunction syndrome (CDS) refers to unsuccessful brain aging with AD-like cognitive decline in elderly pets. CDS encompasses behavioral (i.e., neuropsychological) [16][17][18] and physical signs [19][20]. The neuropsychological signs of canine and feline CDS are well described and classically summarized with the acronym D.I.S.H.A. that stands for Disorientation, altered Interactions, Sleep-wake cycle changes, breaking in the House soiling and altered Activity levels with newly onset anxiety [17][18][21][22][23]. Disorientation, or confusional mental status, is a common finding (over half of the cases), with affected dogs mainly showing aimless stereotypic wandering or stopping in front of the wrong edge of the front door. Vocalization and staring at the empty space as well as getting “stuck” in corners or narrow places are further frequent signs (Figure 1).

Animals 11 02584 g001 550
Figure 1. Old dogs often appear confused or disoriented. Getting “stuck” under furniture without apparently knowing how to get out from there (A) or standing headfirst in corners or tight spaces (B) are common signs of canine CDS.(photo by Lorenzo Golini)

Altered interaction with owners is reported in about 50% of CDS dogs, and increased aggressive behavior can also be observed, albeit less frequently [24]. Sleep-wake cycle disturbance is one of the commonest clinical features and is characterized by an extremely altered REM cycle with frequent awakening during the night and increased daytime sleep [25]. Lost housetraining has been reported in about one-third of CDS patients, and in 16%, active soiling could be observed. Altered emotions with increased novelty anxiety are also frequently detected [17][18][22]. The main neurobehavioral signs of canine CDS are summarized in Table 1.

Table 1. Main clinical signs associated with canine cognitive dysfunction syndrome. The behavioral and clinical categories are shown in bold.
Mental status and spatial orientation (confusional status)
Get lost in a known environment
Awaiting the door opening on the wrong side
Inability to circumnavigate unknown objects
Less interested in environmental stimuli
Relationships (social interaction)
Less interested in being touched
Ignoring the return of the owner
Social behavior is disrupted
Increased need for physical contact (is “needy”)
Activity (increased—repetitive)
Starring at objects or empty space, fly biting
Aimless walking
Increased licking behavior (on the owner or objects)
Increased vocalization
Activity (diminished)
Apathetic, less interested in exploring
Seems to not be interested anymore in known stimuli
Appetite
Eats more than usual
Eats less than usual
Toileting behavior
Reduced time spent cleaning itself
Anxiety (irritability)
Often irritable or anxious
Shows signs of separation anxiety that has never had before
Easily irritable
Sleep—awake cycle
Short period of sleep interrupted by frequent abrupt awakenings
Sleeps more than usual during daytime
Learning and memory
Loss of housetraining, urinating or defecating in front of the owner
Does not request to go out anymore
Despite regular daily activity eliminates only when back home
Eliminates where it sleepsIt is incontinent
Learned behavior and commands
Struggle in performing a previously learned task
Struggle to recognize a member of the family or other known people/animals
Struggle to respond to commands
Struggle to learn new commands or tasks

A very interesting clinical parallelism with AD in human beings is the recognition of an intermediate phase between clinical normal aging subjects and clinically demented pets. This intermediate step has also been named mild cognitive impairment (MCI), borrowing it from human medicine [21][22]. MCI has been defined as reduced cognitive ability without significant interference with daily life [26]. A recent study showed that dogs with MCI exhibit reduced social interaction and novelty fear without signs of breaking of the housetraining nor sleep–awake cycle disturbance [22].

On the physical side of CDS, a large web-based survey recently performed in dogs aged 10 years or older found that vision impairment, smell disturbance, tremor, swaying or falling, and head ptosis were the main physical disturbances related to CDS [20]. Interestingly, similar signs are also prevalent in demented human patients [27] and extrapyramidal signs within an MCI state are predictive of faster progression to full dementia [28]. In this context, it is noteworthy that dogs with CDS were found to be twice as likely to show neurologic deficits compared to “successfully aging” dogs [19].

3. The Role of Astrocytes, Microglia, and CNS Mast Cells in Alzheimer’s Disease

Accumulated evidence suggests that AD pathogenesis is not limited to the neuronal compartment but comprises important interactions with immunological mechanisms in the central nervous system (CNS). It is now well accepted that neuroinflammation contributes to AD pathology. Neuroinflammation is driven by the activation of different brain cells, mainly microglia, astrocytes, and CNS mast cells. If the activity of these cells is under control, neuroinflammation operates correctly and then is turned off. On the contrary, if cell responses escape the physiological control systems, neuroinflammation remains “on” fostering pathological conditions, such as cognitive dysfunction and chronic pain (Figure 2).

Animals 11 02584 g004 550
Figure 2. In response to age-related brain injuries, CNS immune cells (i.e., astrocytes, microglia, and mast cells) become activated and undergo profound morpho-functional changes toward a reactive phenotype. If the resulting release of pro-inflammatory mediators is not properly controlled, non-resolving neuroinflammation may begin. Under this condition, progressive dysfunction at the synaptic and neurovascular level occurs and ultimately leads to homeostatic imbalance and unsuccessful brain aging (i.e., impairments of cognitive and behavioral function).

Microglia modifications have also been described in humans, where the presence of microglial activation and proliferation in several brain regions of AD patients have been observed [134–137]. Very recently, a study in family-owned domestic dogs with CDS has shown a statistically significant increase of microglial numbers in CDS dogs compared to age-match controls [29]. Moreover, signs of microglia hypertrophy and activation were also observed [138]. Studies over the last twenty years have progressively brought to light the involvement of glial reactivity and inflammation in AD, even if the underpinning molecular mechanisms have not yet been fully clarified. For a long while, it was believed that glial cells acquire a reactive phenotype and foster inflammation upon β-amyloid deposition or neurodegeneration. Nowadays, accumulated evidence indicates that reactive gliosis and inflammation occur in the very early phase of the disease before histopathological modifications [30][31][32][33]. On the contrary, other studies on rodent models of AD indicate that the early astroglia response is represented by cell atrophy that may have important consequences for synaptic connectivity, thereby contributing to cognitive deficits [34][35][36][37][38]. These signs of atrophy appear first in the entorhinal cortex and affect astrocytes located afar from senile plaques in the later stages of AD.

Some authors have hypothesized that mast cells are one of the first brain cells that sense amyloid peptides, thus exerting an important role in AD onset and (possibly) progression [39][40]. In agreement, post-mortem studies have shown mast cells surround amyloid plaques in AD patients in higher numbers in comparison to age-matched control patients [41]. The evidence available so far, although limited, supports a possible role for mast cells in AD pathology [42] and opens exciting new fields of research for neuroscientists.

Overall, mast cells, as well as microglia and astrocytes, are now considered critical effectors during several neuroinflammatory disorders, including AD [43]. The modulation of the crosstalk between mast cells and glial cells is emerging as a valuable approach to treat these brain pathologies [42][44][45].

4. Pro-Resolving Mediators in the Resolution of Age-Related Neuroinflammation

Recently, endocannabinoids and their lipid congeners are emerging as pro-resolving agents due to their ability to stimulate resolving programs during neuroinflammation [46][47][48]. Among these compounds, great attention had been focused on palmitoylethanolamide (PEA), an anandamide congener. PEA is an endogenous lipid compound, an amide of ethanolamide and palmitic acid, firstly isolated from soy lecithin [49]. Interestingly, PEA is able to modulate the activity of both glial and mast cells, thus representing a very promising therapeutic tool to treat neurological disorders [217]. These effects are likely due to the ability of PEA to interact with the endocannabinoid system [223] and partially involve the CB2 receptor [222]. Under some circumstances, PEA may potentiate the actions of the canonical endocannabinoids, AEA and 2-AG, by increasing their levels [224]. In addition to these mechanisms, experiments using selective antagonists and murine models where PPAR-α was genetically ablated indicate that the anti-inflammatory and neuroprotective properties of PEA involve the activations of PPAR-α [180,210,227–229].

Through PPAR-α, PEA attenuated in vitro and in vivo β-amyloid-induced glial over-reactivity and the release of pro-inflammatory mediators, including inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α [50][51][52][53][54][55]. PEA also promoted neuronal viability in primary astrocytes derived from the prefrontal cortex of 3xTg-AD mice, a transgenic murine model of AD [56]. All these data concur to demonstrate the key role of PPAR-α in controlling neuroprotective and anti-inflammatory pathways [57]. Moreover, studies showed that the protective effects exerted by PEA also include the activation of GPR55 [58] and TRPV1 [59]. Figure 3 summarizes the proposed mechanisms of action of PEA.

Animals 11 02584 g006 550
Figure 3. Proposed mechanisms of action of PEA. PEA exerts a direct and indirect agonism on the endocannabinoidome within brain cells. The direct pathway depends on the activation of GPR55, TRPV1, and PPAR-α receptors, the last inhibiting the hallmarks of age-related cognitive dysfunction (right panel). Through the so-called entourage effect, PEA may also increase the level (left panel) or the binding affinity of endocannabinoids for CB1 and CB2 receptors, favoring stronger LTP (Long Term Potentiation) and memory processes. See text for further details.

The reduction of endogenous levels of PEA during conditions characterized by non-resolving neuroinflammation, such as unsuccessful brain aging, suggests the opportunity to restore PEA endogenous reserves, thus fostering and re-activating physiological pro-resolving responses.

In order to overcome the low bioavailability of PEA following oral administration, its particle size has been reduced through micronization techniques giving rise to the so-called ultramicronized (um)-PEA. The pharmacological potential of um-PEA in controlling neuroinflammation — either singly or co-ultramicronized with the antioxidant luteolin (i.e., co-ultra PEA) — has been proven by numerous investigations in various models of neurodegenerative conditions and senile dementia, both in vitro and in vivo [60][61][62][63][64]. In rat hippocampal slices and neuroblastoma cells challenged with β-amyloid 1–42, PEA in the ultramicronized or co-ultramicronized formulation exhibited anti-inflammatory and anti-apoptotic effects, as well as the ability to decrease the expression of markers of oxidative stress and astroglial injuries, such as iNOS and GFAP [65][66]. In rats that received an intrahippocampal infusion of β-amyloid 1–42, chronic treatment for 14 days with co-ultra PEA prevented astrocyte hypertrophy as well as the production of pro-inflammatory cytokines and enzymes, compared to vehicle-treated animals [67]. Moreover, in this AD model, co-ultra PEA also prevented the decrease in gene expression of glial-derived and brain-derived neurotrophins [68]. In 3xTg-AD mice, i.e., an animal model of AD exhibiting age-dependent β-amyloid and tau pathologies, chronic administration of um-PEA reduced brain levels of several pro-inflammatory mediators and showed neuroprotective effects [33][56][69][70]. Importantly, um-PEA also prevented the impaired performance in cognitive tasks as well as reduced the AD-like pathology in these animals, as shown by the decrease of β-amyloid formation and tau protein phosphorylation in the hippocampus [33].

References

  1. Scherbov, S.; Sanderson, W.C. New Approaches to the Conceptualization and Measurement of Age and Ageing. In Developments in Demographic Forecasting; The Springer Series on Demographic Methods and Population, Analysis; Mazzuco, S., Keilman, N., Eds.; Springer International Publishing: Cham, Switzerland, 2020; pp. 243–258.
  2. Gunn-Moore, D. Considering older cats. J. Small Anim. Pract. 2006, 47, 430–431.
  3. Quimby, J.; Gowland, S.; Carney, H.C.; DePorter, T.; Plummer, P.; Westropp, J. 2021 AAHA/AAFP Feline Life Stage Guidelines. J. Feline Med. Surg. 2021, 23, 211–233.
  4. Creevy, K.E.; Grady, J.; Little, S.E.; Moore, G.E.; Strickler, B.G.; Thompson, S.; Webb, J.A. 2019 AAHA Canine Life Stage Guidelines. J. Am. Anim. Hosp. Assoc. 2019, 55, 267–290.
  5. Urtamo, A.; Jyväkorpi, S.; Strandberg, T. Definitions of successful ageing: A brief review of a multidimensional concept. Acta Biomed. Atenei Parm. 2019, 90, 359–363.
  6. McCune, S.; Stevenson, J.; Fretwell, L.; Thompson, A.; Mills, D.S. Ageing does not significantly affect performance in a spatial learning task in the domestic cat (felis silvestris catus). Appl. Anim. Behav. Sci. 2008, 112, 345–356.
  7. Chapagain, D.; Range, F.; Huber, L.; Virányi, Z. Cognitive Aging in Dogs. Gerontology 2017, 64, 165–171.
  8. Salvin, H.E.; McGreevy, P.D.; Sachdev, P.; Valenzuela, M. Growing old gracefully—Behavioral changes associated with “successful aging” in the dog, Canis familiaris. J. Vet. Behav. 2011, 6, 313–320.
  9. González-Martínez, I.; Rosado, B.; Pesini, P.; García-Belenguer, S.; Palacio, J.; Villegas, A.; Suárez, M.-L.; Santamarina, G.; Sarasa, M. Effect of age and severity of cognitive dysfunction on two simple tasks in pet dogs. Vet. J. Lond. Engl. 1997, 198, 176–181.
  10. Mongillo, P.; Pitteri, E.; Carnier, P.; Gabai, G.; Adamelli, S.; Marinelli, L. Does the attachment system towards owners change in aged dogs? Physiol. Behav. 2013, 120, 64–69.
  11. Turcsán, B.; Wallis, L.; Berczik, J.; Range, F.; Kubinyi, E.; Virányi, Z. Individual and group level personality change across the lifespan in dogs. Sci. Rep. 2020, 10, 1–12.
  12. Van Bourg, J.; Gilchrist, R.; Wynne, C.D.L. Adaptive spatial working memory assessments for aging pet dogs. Anim. Cogn. 2020, 24, 511–531.
  13. Mongillo, P.; Araujo, J.A.; Pitteri, E.; Carnier, P.; Adamelli, S.; Regolin, L.; Marinelli, L. Spatial reversal learning is impaired by age in pet dogs. AGE Dordr. Neth. 2013, 35, 2273–2282.
  14. Banzato, T.; Franzo, G.; Di Maggio, R.; Nicoletto, E.; Burti, S.; Cesari, M.; Canevelli, M. A Frailty Index based on clinical data to quantify mortality risk in dogs. Sci. Rep. 2019, 9, 1–9.
  15. Ray, M.; Carney, H.C.; Boynton, B.; Quimby, J.; Robertson, S.; Denis, K.S.; Tuzio, H.; Wright, B. 2021 AAFP Feline Senior Care Guidelines. J. Feline Med. Surg. 2021, 23, 613–638.
  16. Ruehl, W.; Bruyette, D.; DePaoli, A.; Cotman, C.; Head, E.; Milgram, N.; Cummings, B. Chapter 22 Canine cognitive dysfunction as a model for human age-related cognitive decline, dementia and Alzheimer’s disease: Clinical presentation, cognitive testing, pathology and response to 1-deprenyl therapy. Prog. Brain Res. 1995, 106, 217–225.
  17. Siwak, C.T.; Tapp, P.D.; Milgram, N.W. Effect of Age and Level of Cognitive Function on Spontaneous and Exploratory Behaviors in the Beagle Dog. Learn. Mem. 2001, 8, 317–325.
  18. Fast, R.; Schütt, T.; Toft, N.; Møller, A.; Berendt, M. An Observational Study with Long-Term Follow-Up of Canine Cognitive Dysfunction: Clinical Characteristics, Survival, and Risk Factors. J. Vet. Intern. Med. 2013, 27, 822–829.
  19. Golini, L.; Colangeli, R.; Tranquillo, V.; Mariscoli, M. Association between neurologic and cognitive dysfunction signs in a sample of aging dogs. J. Vet. Behav. 2009, 4, 25–30.
  20. Ozawa, M.; Inoue, M.; Uchida, K.; Chambers, J.; Takeuch, Y.; Nakayama, H. Physical signs of canine cognitive dysfunction. J. Vet. Med. Sci. 2019, 81, 1829–1834.
  21. Salvin, H.E.; McGreevy, P.D.; Sachdev, P.S.; Valenzuela, M.J. The canine cognitive dysfunction rating scale (CCDR): A data-driven and ecologically relevant assessment tool. Vet. J. Lond. Engl. 1997, 188, 331–336.
  22. Vikartovska, Z.; Farbakova, J.; Smolek, T.; Hanes, J.; Zilka, N.; Hornakova, L.; Humenik, F.; Maloveska, M.; Hudakova, N.; Cizkova, D. Novel Diagnostic Tools for Identifying Cognitive Impairment in Dogs: Behavior, Biomarkers, and Pathology. Front. Vet. Sci. 2021, 7, 551895.
  23. Gunn-Moore, D.; Moffat, K.; Christie, L.-A.; Head, E. Cognitive dysfunction and the neurobiology of ageing in cats. J. Small Anim. Pr. 2007, 48, 546–553.
  24. Landsberg, G.M.; Malamed, R. Clinical Picture of Canine and Feline Cognitive Impairment. In Canine and Feline Dementia: Molecular Basis, Diagnostics and Therapy; Landsberg, G., Maďari, A., Žilka, N., Eds.; Springer International Publishing: Cham, Switzerland, 2017; pp. 1–12.
  25. Takeuchi, T.; Harada, E. Age-related changes in sleep-wake rhythm in dog. Behav. Brain Res. 2002, 136, 193–199.
  26. De Mendonça, A.; Ribeiro, F.; Guerreiro, M.; Palma, T.; Garcia, C.; Mendonca, A. Clinical significance of subcortical vascular disease in patients with mild cognitive impairment. Eur. J. Neurol. 2005, 12, 125–130.
  27. Urbanowitsch, N.; Degen, C.; Toro, P.; Schröder, J. Neurological Soft Signs in Aging, Mild Cognitive Impairment, and Alzheimer’s Disease—The Impact of Cognitive Decline and Cognitive Reserve. Front. Psychiatry 2015, 6, 12.
  28. Boyle, P.A.; Wilson, R.S.; Aggarwal, N.T.; Arvanitakis, Z.; Kelly, J.; Bienias, J.L.; Bennett, D.A. Parkinsonian signs in subjects with mild cognitive impairment. Neurology 2005, 65, 1901–1906.
  29. Thomsen, B.B.; Madsen, C.; Krohn, K.T.; Thygesen, C.; Schütt, T.; Metaxas, A.; Darvesh, S.; Agerholm, J.S.; Wirenfeldt, M.; Berendt, M.; et al. Mild Microglial Responses in the Cortex and Perivascular Macrophage Infiltration in Subcortical White Matter in Dogs with Age-Related Dementia Modelling Prodromal Alzheimer’s Disease. J. Alzheimers Dis. 2021, 82, 575–592.
  30. Hoozemans, J.J.M.; Rozemuller, A.J.M.; Van Haastert, E.S.; Eikelenboom, P.; Van Gool, W. Neuroinflammation in Alzheimer’s disease wanes with age. J. Neuroinflammation 2011, 8, 171.
  31. King, E.; O’Brien, J.; Donaghy, P.; Morris, C.; Barnett, N.; Olsen, K.; Martin-Ruiz, C.; Taylor, J.-P.; Thomas, A.J. Peripheral inflammation in prodromal Alzheimer’s and Lewy body dementias. J. Neurol. Neurosurg. Psychiatry 2017, 89, 339–345.
  32. Kummer, M.P.; Hammerschmidt, T.; Martinez, A.; Terwel, D.; Eichele, G.; Witten, A.; Figura, S.; Stoll, M.; Schwartz, S.; Pape, H.-C.; et al. Ear2 Deletion Causes Early Memory and Learning Deficits in APP/PS1 Mice. J. Neurosci. Off. J. Soc. Neurosci. 2014, 34, 8845–8854.
  33. Scuderi, C.; Bronzuoli, M.R.; Facchinetti, R.; Pace, L.; Ferraro, L.; Broad, K.D.; Serviddio, G.; Bellanti, F.; Palombelli, G.; Carpinelli, G.; et al. Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer’s disease by exerting anti-inflammatory and neuroprotective effects. Transl. Psychiatry 2018, 8, 32.
  34. Olabarria, M.; Noristani, H.; Verkhratsky, A.; Rodríguez, J.J. Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer’s disease. Glia 2010, 58, 831–838.
  35. Olabarria, M.; Noristani, H.; Verkhratsky, A.; Rodríguez, J.J. Age-dependent decrease in glutamine synthetase expression in the hippocampal astroglia of the triple transgenic Alzheimer’s disease mouse model: Mechanism for deficient glutamatergic transmission? Mol. Neurodegener. 2011, 6, 55.
  36. Yeh, C.-Y.; Vadhwana, B.; Verkhratsky, A.; Rodriguez, J.J. Early Astrocytic Atrophy in the Entorhinal Cortex of a Triple Transgenic Animal Model of Alzheimer’s Disease. ASN Neuro 2011, 3, 271–279.
  37. Kulijewicz-Nawrot, M.; Verkhratsky, A.; Chvatal, A.; Syková, E.; Rodríguez, J.J. Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease. J. Anat. 2012, 221, 252–262.
  38. Beauquis, J.; Pavía, P.; Pomilio, C.; Vinuesa, A.; Podlutskaya, N.; Galvan, V.; Saravia, F. Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer’s disease. Exp. Neurol. 2013, 239, 28–37.
  39. Harcha, P.A.; Vargas, A.; Yi, C.; Koulakoff, A.A.; Giaume, C.; Sáez, J.C. Hemichannels Are Required for Amyloid -Peptide-Induced Degranulation and Are Activated in Brain Mast Cells of APPswe/PS1dE9 Mice. J. Neurosci. 2015, 35, 9526–9538.
  40. Shaik-Dasthagirisaheb, Y.B.; Conti, P. The Role of Mast Cells in Alzheimer’s Disease. Adv. Clin. Exp. Med. Off. Organ. Wroc. Med. Univ. 2016, 25, 781–787.
  41. Maslinska, D.; Laure-Kamionowska, M.; Maslinski, K.T.; Gujski, M.; Maslinski, S. Distribution of tryptase-containing mast cells and metallothionein reactive astrocytes in human brains with amyloid deposits. Inflamm. Res. 2007, 56, S17–S18.
  42. Skaper, S.D.; Facci, L.; Zusso, M.; Giusti, P. An Inflammation-Centric View of Neurological Disease: Beyond the Neuron. Front. Cell. Neurosci. 2018, 12, 72.
  43. Harcha, P.A.; Garcés, P.; Arredondo, C.; Fernández, G.; Sáez, J.C.; van Zundert, B. Mast Cell and Astrocyte Hemichannels and Their Role in Alzheimer’s Disease, ALS, and Harmful Stress Conditions. Int. J. Mol. Sci. 2021, 22, 1924.
  44. Dong, H.; Zhang, X.; Wang, Y.; Zhou, X.; Qian, Y.; Zhang, S. Suppression of Brain Mast Cells Degranulation Inhibits Microglial Activation and Central Nervous System Inflammation. Mol. Neurobiol. 2016, 54, 997–1007.
  45. Dong, H.; Wang, Y.; Zhang, X.; Zhang, X.; Qian, Y.; Ding, H.; Zhang, S. Stabilization of Brain Mast Cells Alleviates LPS-Induced Neuroinflammation by Inhibiting Microglia Activation. Front. Cell. Neurosci. 2019, 13, 191.
  46. Mecha, M.; Carrillo-Salinas, F.J.; Feliu, A.; Mestre, L.; Guaza, C. Microglia activation states and cannabinoid system: Therapeutic implications. Pharmacol. Ther. 2016, 166, 40–55.
  47. Skaper, S.D.; Facci, L.; Barbierato, M.; Zusso, M.; Bruschetta, G.; Impellizzeri, D.; Cuzzocrea, S.; Giusti, P. N-Palmitoylethanolamine and Neuroinflammation: A Novel Therapeutic Strategy of Resolution. Mol. Neurobiol. 2015, 52, 1034–1042.
  48. Gokoh, M.; Kishimoto, S.; Oka, S.; Sugiura, T. 2-Arachidonoylglycerol Enhances the Phagocytosis of Opsonized Zymosan by HL-60 Cells Differentiated into Macrophage-Like Cells. Biol. Pharm. Bull. 2007, 30, 1199–1205.
  49. Gugliandolo, E.; Peritore, A.F.; Piras, C.; Cuzzocrea, S.; Crupi, R. Palmitoylethanolamide and Related ALIAmides: Prohomeostatic Lipid Compounds for Animal Health and Wellbeing. Vet. Sci. 2020, 7, 78.
  50. Scuderi, C.; Stecca, C.; Valenza, M.; Ratano, P.; Bronzuoli, M.R.; Bartoli, S.; Pompili, E.; Fumagalli, L.; Campolongo, P.; Steardo, L. Palmitoylethanolamide controls reactive gliosis and exerts neuroprotective functions in a rat model of Alzheimer’s disease. Cell Death Dis. 2014, 5, e1419-e1419.
  51. Scuderi, C.; Steardo, L. Neuroglial Roots of Neurodegenerative Diseases: Therapeutic Potential of Palmitoylethanolamide in Models of Alzheimer’s Disease. CNS Neurol. Disord. Drug Targets 2013, 12, 62–69.
  52. Scuderi, C.; Esposito, G.; Blasio, A.; Valenza, M.; Arietti, P.; Steardo, L., Jr.; Carnuccio, R.; De Filippis, D.; Petrosino, S.; Iuvone, T.; et al. Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide. J. Cell. Mol. Med. 2011, 15, 2664–2674.
  53. Cipriano, M.; Esposito, G.; Negro, L.; Capoccia, E.; Sarnelli, G.; Scuderi, C.; De Filippis, D.; Steardo, L.; Iuvone, T. Palmitoylethanolamide Regulates Production of Pro-Angiogenic Mediators in a Model of β Amyloid-Induced Astrogliosis In Vitro. CNS Neurol. Disord. Drug Targets 2015, 14, 828–837.
  54. Beggiato, S.; Borelli, A.C.; Ferraro, L.; Tanganelli, S.; Antonelli, T.; Tomasini, M.C. Palmitoylethanolamide Blunts Amyloid-β42-Induced Astrocyte Activation and Improves Neuronal Survival in Primary Mouse Cortical Astrocyte-Neuron Co-Cultures. J. Alzheimers Dis. 2017, 61, 389–399.
  55. Beggiato, S.; Cassano, T.; Ferraro, L.; Tomasini, M.C. Astrocytic palmitoylethanolamide pre-exposure exerts neuroprotective effects in astrocyte-neuron co-cultures from a triple transgenic mouse model of Alzheimer’s disease. Life Sci. 2020, 257, 118037.
  56. Bronzuoli, M.R.; Facchinetti, R.; Steardo, L.; Romano, A.; Stecca, C.; Passarella, S.; Cassano, T.; Scuderi, C. Palmitoylethanolamide Dampens Reactive Astrogliosis and Improves Neuronal Trophic Support in a Triple Transgenic Model of Alzheimer’s Disease: In Vitro and In Vivo Evidence. Oxidative Med. Cell. Longev. 2018, 2018, 1–14.
  57. Wójtowicz, S.; Strosznajder, J.B.; Jeżyna, M. The Novel Role of PPAR Alpha in the Brain: Promising Target in Therapy of Alzheimer’s Disease and Other Neurodegenerative Disorders. Neurochem. Res. 2020, 45, 972–988.
  58. Pertwee, R.G. GPR55: A new member of the cannabinoid receptor clan? Br. J. Pharmacol. 2007, 152, 984–986.
  59. Zygmunt, P.M.; Ermund, A.; Movahed, P.; Andersson, D.; Simonsen, C.; Jönsson, B.; Blomgren, A.; Birnir, B.; Bevan, S.J.; Eschalier, A.; et al. Monoacylglycerols Activate TRPV1—A Link between Phospholipase C and TRPV1. PLoS ONE 2013, 8, e81618.
  60. Caltagirone, C.; Stroke Study Group; Cisari, C.; Schievano, C.; di Paola, R.; Cordaro, M.; Bruschetta, G.; Esposito, E.; Cuzzocrea, S. Co-ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: From Rodent to Man. Transl. Stroke Res. 2015, 7, 54–69.
  61. Cordaro, M.; Impellizzeri, D.; Paterniti, I.; Bruschetta, G.; Siracusa, R.; De Stefano, D.; Cuzzocrea, S.; Esposito, E. Neuroprotective Effects of Co-UltraPEALut on Secondary Inflammatory Process and Autophagy Involved in Traumatic Brain Injury. J. Neurotrauma 2016, 33, 132–146.
  62. Crupi, R.; Paterniti, I.; Ahmad, A.; Campolo, M.; Esposito, E.; Cuzzocrea, S. Effects of Palmitoylethanolamide and Luteolin in an Animal Model of Anxiety/Depression. CNS Neurol. Disord. Drug Targets 2013, 12, 989–1001.
  63. Beggiato, S.; Tomasini, M.C.; Ferraro, L. Palmitoylethanolamide (PEA) as a Potential Therapeutic Agent in Alzheimer’s Disease. Front. Pharmacol. 2019, 10, 821.
  64. Petrosino, S.; Moriello, A.S. Palmitoylethanolamide: A Nutritional Approach to Keep Neuroinflammation within Physiological Boundaries. A Systematic Review. Int. J. Mol. Sci. 2020, 21, 9526.
  65. Phochantachinda, S.; Chantong, B.; Reamtong, O.; Chatchaisak, D. Change in the plasma proteome associated with canine cognitive dysfunction syndrome (CCDS) in Thailand. BMC Vet. Res. 2021, 17, 1–14.
  66. Bradshaw, E.M.; Initiative, T.A.D.N.; Chibnik, L.B.; Keenan, B.T.; Ottoboni, L.; Raj, T.; Tang, A.; Rosenkrantz, L.L.; Imboywa, S.; Lee, M.; et al. CD33 Alzheimer’s disease locus: Altered monocyte function and amyloid biology. Nat. Neurosci. 2013, 16, 848–850.
  67. Paterniti, I.; Cordaro, M.; Campolo, M.; Siracusa, R.; Cornelius, C.; Navarra, M.; Cuzzocrea, S.; Esposito, E. Neuroprotection by Association of Palmitoylethanolamide with Luteolin in Experimental Alzheimer’s Disease Models: The Control of Neuroinflammation. CNS Neurol. Disord. Drug Targets 2014, 13, 1530–1541.
  68. Facchinetti, R.; Valenza, M.; Bronzuoli, M.R.; Menegoni, G.; Ratano, P.; Steardo, L.; Campolongo, P.; Scuderi, C. Looking for a Treatment for the Early Stage of Alzheimer’s Disease: Preclinical Evidence with Co-Ultramicronized Palmitoylethanolamide and Luteolin. Int. J. Mol. Sci. 2020, 21, 3802.
  69. Beggiato, S.; Tomasini, M.C.; Cassano, T.; Ferraro, L. Chronic Oral Palmitoylethanolamide Administration Rescues Cognitive Deficit and Reduces Neuroinflammation, Oxidative Stress, and Glutamate Levels in A Transgenic Murine Model of Alzheimer’s Disease. J. Clin. Med. 2020, 9, 428.
  70. Cassano, T.; Bellanti, F.; Bukke, V.N.; Archana, M.; Scuderi, C.; Ferraro, L.; Serviddio, G.; Cuomo, V. Effects of Ultramicronized Palmitoylethanolamide Treatment on the Glutamatergic Alterations and Mitochondrial Impairment In 3 × Tg-Ad Mice. Pharmadvances 2021, 3, 87–88.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY)license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Neurosciences
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Caterina Scuderi
View Times: 232
Revisions: 2 times (View History)
Update Date: 18 Sep 2021
Table of Contents
    1000/1000
    Hot Most Recent
    Feedback