In situ stoichiometry amounts of p62 and poly-ubiquitin exceed the increase of alpha-synuclein during degeneration of catecholamine cells induced by autophagy inhibition in vitro.

Neurodegenerative disorders are typically featured by the occurrence of neuronal inclusions. In the case of Parkinson's disease (PD) these correspond to Lewy bodies (LBs), which are routinely defined as proteinaceous inclusions composed of alpha-synuclein (alpha-syn). In turn, alpha-syn is considered to be the key protein in producing PD and fostering its progression. Recent studies challenged such a concept and emphasized the occurrence of other proteins such as p62 and poly-ubiquitin (Poly-ub) in the composition of LBs, which are also composed of large amounts of tubulo-vesicular structures. All these components, which accumulate within the cytosol of affected neurons in PD, may be the consequence of a dysfunction of major clearing pathways. In fact, autophagy-related systems are constantly impaired in inherited PD and genetic models of PD. The present study was designed to validate whether a pharmacological inhibition of autophagy within catecholamine cells produces cell damage and accumulation of specific proteins and tubulo-vesicular structures. The stoichiometry counts of single proteins, which accumulate within catecholamine neurons was carried out along with the area of tubulo-vesicular structures. In these experimental conditions p62 and Poly-ub accumulation exceeded at large the amounts of alpha-syn. In those areas where Poly-ub and p62 were highly expressed, tubulo-vesicular structures were highly represented compared with surrounding cytosol. The present study confirms new vistas about LBs composition and lends substance to the scenario that autophagy inhibition rather than a single protein dysfunction as key determinant of PD.

Is There a Place for Lewy Bodies before and beyond Alpha-Synuclein Accumulation? Provocative Issues in Need of Solid Explanations.

In the last two decades, alpha-synuclein (alpha-syn) assumed a prominent role as a major component and seeding structure of Lewy bodies (LBs). This concept is driving ongoing research on the pathophysiology of Parkinson's disease (PD). In line with this, alpha-syn is considered to be the guilty protein in the disease process, and it may be targeted through precision medicine to modify disease progression. Therefore, designing specific tools to block the aggregation and spreading of alpha-syn represents a major effort in the development of disease-modifying therapies in PD. The present article analyzes concrete evidence about the significance of alpha-syn within LBs. In this effort, some dogmas are challenged. This concerns the question of whether alpha-syn is more abundant compared with other proteins within LBs. Again, the occurrence of alpha-syn compared with non-protein constituents is scrutinized. Finally, the prominent role of alpha-syn in seeding LBs as the guilty structure causing PD is questioned. These revisited concepts may be helpful in the process of validating which proteins, organelles, and pathways are likely to be involved in the damage to meso-striatal dopamine neurons and other brain regions involved in PD.

Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration.

The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer's dementia (AD) and Parkinson's disease (PD), damage to the locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented and hypothesized to foster the onset and progression of neurodegeneration within target regions. Specifically, the present experiments were designed to assess whether selective damage to LC-NE axons may alter key proteins involved in neurodegeneration within specific limbic regions, such as the hippocampus and piriform cortex, compared with the dorsal striatum. To achieve this, a loss of LC-NE axons was induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in C57 Black mice, as assessed by a loss of NE and dopamine-beta-hydroxylase within target regions. In these experimental conditions, the amount of alpha-synuclein (alpha-syn) protein levels were increased along with alpha-syn expressing neurons within the hippocampus and piriform cortex. Similar findings were obtained concerning phospho-Tau immunoblotting. In contrast, a decrease in inducible HSP70-expressing neurons and a loss of sequestosome (p62)-expressing cells, along with a loss of these proteins at immunoblotting, were reported. The present data provide further evidence to understand why a loss of LC-NE axons may foster limbic neurodegeneration in AD and limbic engagement during PD.

Combined light and electron microscopy (CLEM) to quantify methamphetamine-induced alpha-synuclein-related pathology.

Methamphetamine (METH) produces a cytopathology, which is rather specific within catecholamine neurons both in vitro and ex vivo, in animal models and chronic METH abusers. This led some authors to postulate a sort of parallelism between METH cytopathology and cell damage in Parkinson's disease (PD). In fact, METH increases and aggregates alpha-syn proto-fibrils along with producing spreading of alpha-syn. Although alpha-syn is considered to be the major component of aggregates and inclusions developing within diseased catecholamine neurons including classic Lewy body (LB), at present, no study provided a quantitative assessment of this protein in situ, neither following METH nor in LB occurring in PD. Similarly, no study addressed the quantitative comparison between occurrence of alpha-syn and other key proteins and no investigation measured the protein compared with non-protein structure within catecholamine cytopathology. Therefore, the present study addresses these issues using an oversimplified model consisting of a catecholamine cell line where the novel approach of combined light and electron microscopy (CLEM) was used measuring the amount of alpha-syn, which is lower compared with p62 or poly-ubiquitin within pathological cell domains. The scenario provided by electron microscopy reveals unexpected findings, which are similar to those recently described in the pathology of PD featuring packing of autophagosome-like vesicles and key proteins shuttling autophagy substrates. Remarkably, small seed-like areas, densely packed with p62 molecules attached to poly-ubiquitin within wide vesicular domains occurred. The present data shed new light about quantitative morphometry of catecholamine cell damage in PD and within the addicted brain.

The Relevance of Autophagy within Inner Ear in Baseline Conditions and Tinnitus-Related Syndromes.

Tinnitus is the perception of noise in the absence of acoustic stimulation (phantom noise). In most patients suffering from chronic peripheral tinnitus, an alteration of outer hair cells (OHC) starting from the stereocilia (SC) occurs. This is common following ototoxic drugs, sound-induced ototoxicity, and acoustic degeneration. In all these conditions, altered coupling between the tectorial membrane (TM) and OHC SC is described. The present review analyzes the complex interactions involving OHC and TM. These need to be clarified to understand which mechanisms may underlie the onset of tinnitus and why the neuropathology of chronic degenerative tinnitus is similar, independent of early triggers. In fact, the fine neuropathology of tinnitus features altered mechanisms of mechanic-electrical transduction (MET) at the level of OHC SC. The appropriate coupling between OHC SC and TM strongly depends on autophagy. The involvement of autophagy may encompass degenerative and genetic tinnitus, as well as ototoxic drugs and acoustic trauma. Defective autophagy explains mitochondrial alterations and altered protein handling within OHC and TM. This is relevant for developing novel treatments that stimulate autophagy without carrying the burden of severe side effects. Specific phytochemicals, such as curcumin and berberin, acting as autophagy activators, may mitigate the neuropathology of tinnitus.

Autophagy Activation Promoted by Pulses of Light and Phytochemicals Counteracting Oxidative Stress during Age-Related Macular Degeneration.

The seminal role of autophagy during age-related macular degeneration (AMD) lies in the clearance of a number of reactive oxidative species that generate dysfunctional mitochondria. In fact, reactive oxygen species (ROS) in the retina generate misfolded proteins, alter lipids and sugars composition, disrupt DNA integrity, damage cell organelles and produce retinal inclusions while causing AMD. This explains why autophagy in the retinal pigment epithelium (RPE), mostly at the macular level, is essential in AMD and even in baseline conditions to provide a powerful and fast replacement of oxidized molecules and ROS-damaged mitochondria. When autophagy is impaired within RPE, the deleterious effects of ROS, which are produced in excess also during baseline conditions, are no longer counteracted, and retinal degeneration may occur. Within RPE, autophagy can be induced by various stimuli, such as light and naturally occurring phytochemicals. Light and phytochemicals, in turn, may synergize to enhance autophagy. This may explain the beneficial effects of light pulses combined with phytochemicals both in improving retinal structure and visual acuity. The ability of light to activate some phytochemicals may further extend such a synergism during retinal degeneration. In this way, photosensitive natural compounds may produce light-dependent beneficial antioxidant effects in AMD.

The Essential Role of Light-Induced Autophagy in the Inner Choroid/Outer Retinal Neurovascular Unit in Baseline Conditions and Degeneration.

The present article discusses the role of light in altering autophagy, both within the outer retina (retinal pigment epithelium, RPE, and the outer segment of photoreceptors) and the inner choroid (Bruch's membrane, BM, endothelial cells and the pericytes of choriocapillaris, CC). Here autophagy is needed to maintain the high metabolic requirements and to provide the specific physiological activity sub-serving the process of vision. Activation or inhibition of autophagy within RPE strongly depends on light exposure and it is concomitant with activation or inhibition of the outer segment of the photoreceptors. This also recruits CC, which provides blood flow and metabolic substrates. Thus, the inner choroid and outer retina are mutually dependent and their activity is orchestrated by light exposure in order to cope with metabolic demand. This is tuned by the autophagy status, which works as a sort of pivot in the cross-talk within the inner choroid/outer retina neurovascular unit. In degenerative conditions, and mostly during age-related macular degeneration (AMD), autophagy dysfunction occurs in this area to induce cell loss and extracellular aggregates. Therefore, a detailed analysis of the autophagy status encompassing CC, RPE and interposed BM is key to understanding the fine anatomy and altered biochemistry which underlie the onset and progression of AMD.

Lithium engages autophagy for neuroprotection and neuroplasticity: Translational evidence for therapy.

Here an overview is provided on therapeutic/neuroprotective effects of Lithifum (Li+) in neurodegenerative and psychiatric disorders focusing on the conspicuous action of Li+ through autophagy. The effects on the autophagy machinery remain the key molecular mechanisms to explain the protective effects of Li+ for neurodegenerative diseases, offering potential therapeutic strategies for the treatment of neuropsychiatric disorders and emphasizes a crossroad linking autophagy, neurodegenerative disorders, and mood stabilization. Sensitization by psychostimulants points to several mechanisms involved in psychopathology, most also crucial in neurodegenerative disorders. Evidence shows the involvement of autophagy and metabotropic Glutamate receptors-5 (mGluR5) in neurodegeneration due to methamphetamine neurotoxicity as well as in neuroprotection, both in vitro and in vivo models. More recently, Li+ was shown to modulate autophagy through its action on mGluR5, thus pointing to an additional way of autophagy engagement by Li+ and to a substantial role of mGluR5 in neuroprotection related to neural e neuropsychiatry diseases. We propose Li+ engagement of autophagy through the canonical mechanisms of autophagy machinery and through the intermediary of mGluR5.

Autophagy Activation Associates with Suppression of Prion Protein and Improved Mitochondrial Status in Glioblastoma Cells.

Cells from glioblastoma multiforme (GBM) feature up-regulation of the mechanistic Target of Rapamycin (mTOR), which brings deleterious effects on malignancy and disease course. At the cellular level, up-regulation of mTOR affects a number of downstream pathways and suppresses autophagy, which is relevant for the neurobiology of GBM. In fact, autophagy acts on several targets, such as protein clearance and mitochondrial status, which are key in promoting the malignancy GBM. A defective protein clearance extends to cellular prion protein (PrPc). Recent evidence indicates that PrPc promotes stemness and alters mitochondrial turnover. Therefore, the present study measures whether in GBM cells abnormal amount of PrPc and mitochondrial alterations are concomitant in baseline conditions and whether they are reverted by mTOR inhibition. Proteins related to mitochondrial turnover were concomitantly assessed. High amounts of PrPc and altered mitochondria were both mitigated dose-dependently by the mTOR inhibitor rapamycin, which produced a persistent activation of the autophagy flux and shifted proliferating cells from S to G1 cell cycle phase. Similarly, mTOR suppression produces a long-lasting increase of proteins promoting mitochondrial turnover, including Pink1/Parkin. These findings provide novel evidence about the role of autophagy in the neurobiology of GBM.

Alterations of Mitochondrial Structure in Methamphetamine Toxicity.

Recent evidence shows that methamphetamine (METH) produces mitochondrial alterations that contribute to neurotoxicity. Nonetheless, most of these studies focus on mitochondrial activity, whereas mitochondrial morphology remains poorly investigated. In fact, morphological evidence about the fine structure of mitochondria during METH toxicity is not available. Thus, in the present study we analyzed dose-dependent mitochondrial structural alterations during METH exposure. Light and transmission electron microscopy were used, along with ultrastructural stoichiometry of catecholamine cells following various doses of METH. In the first part of the study cell death and cell degeneration were assessed and they were correlated with mitochondrial alterations observed using light microscopy. In the second part of the study, ultrastructural evidence of specific mitochondrial alterations of crests, inner and outer membranes and matrix were quantified, along with in situ alterations of mitochondrial proteins. Neurodegeneration induced by METH correlates significantly with specific mitochondrial damage, which allows definition of a scoring system for mitochondrial integrity. In turn, mitochondrial alterations are concomitant with a decrease in fission/mitophagy protein Fis1 and DRP1 and an increase in Pink1 and Parkin in situ, at the mitochondrial level. These findings provide structural evidence that mitochondria represent both direct and indirect targets of METH-induced toxicity.

Bacopa Protects against Neurotoxicity Induced by MPP+ and Methamphetamine.

The neurotoxins methamphetamine (METH) and 1-methyl-4-phenylpyridinium (MPP+) damage catecholamine neurons. Although sharing the same mechanism to enter within these neurons, METH neurotoxicity mostly depends on oxidative species, while MPP+ toxicity depends on the inhibition of mitochondrial activity. This explains why only a few compounds protect against both neurotoxins. Identifying a final common pathway that is shared by these neurotoxins is key to prompting novel remedies for spontaneous neurodegeneration. In the present study we assessed whether natural extracts from Bacopa monnieri (BM) may provide a dual protection against METH- and MPP+-induced cell damage as measured by light and electron microscopy. The protection induced by BM against catecholamine cell death and degeneration was dose-dependently related to the suppression of reactive oxygen species (ROS) formation and mitochondrial alterations. These were measured by light and electron microscopy with MitoTracker Red and Green as well as by the ultrastructural morphometry of specific mitochondrial structures. In fact, BM suppresses the damage of mitochondrial crests and matrix dilution and increases the amount of healthy and total mitochondria. The present data provide evidence for a natural compound, which protects catecholamine cells independently by the type of experimental toxicity. This may be useful to counteract spontaneous degenerations of catecholamine cells.

Within the Ischemic Penumbra, Sub-Cellular Compartmentalization of Heat Shock Protein 70 Overlaps with Autophagy Proteins and Fails to Merge with Lysosomes.

The brain area which surrounds the frankly ischemic region is named the area penumbra. In this area, most cells are spared although their oxidative metabolism is impaired. area penumbra is routinely detected by immunostaining of a molecule named Heat Shock Protein 70 (HSP70). Within the area penumbra, autophagy-related proteins also increase. Therefore, in the present study, the autophagy-related microtubule-associated protein I/II-Light Chain 3 (LC3) was investigated within the area penumbra along with HSP70. In C57 black mice, ischemia was induced by permanent occlusion of the distal part of the middle cerebral artery. Immunofluorescence and electron microscopy show that LC3 and HSP70 are overexpressed and co-localize within the area penumbra in the same cells and within similar subcellular compartments. In the area penumbra, marked loss of co-localization of HSP70 and LC3-positive autophagy vacuoles, with lysosomal-associated membrane protein 1 (LAMP1) or cathepsin-D-positive lysosome vacuoles occurs. This study indicates that, within the area penumbra, a failure of autophagolysosomes depends on defective compartmentalization of LC3, LAMP1 and cathepsin-D and a defect in merging between autophagosomes and lysosomes. Such a deleterious effect is likely to induce a depletion of autophagolysosomes and cell clearing systems, which needs to be rescued in the process of improving neuronal survival.

The Baseline Structure of the Enteric Nervous System and Its Role in Parkinson's Disease.

The gastrointestinal (GI) tract is provided with a peculiar nervous network, known as the enteric nervous system (ENS), which is dedicated to the fine control of digestive functions. This forms a complex network, which includes several types of neurons, as well as glial cells. Despite extensive studies, a comprehensive classification of these neurons is still lacking. The complexity of ENS is magnified by a multiple control of the central nervous system, and bidirectional communication between various central nervous areas and the gut occurs. This lends substance to the complexity of the microbiota-gut-brain axis, which represents the network governing homeostasis through nervous, endocrine, immune, and metabolic pathways. The present manuscript is dedicated to identifying various neuronal cytotypes belonging to ENS in baseline conditions. The second part of the study provides evidence on how these very same neurons are altered during Parkinson's disease. In fact, although being defined as a movement disorder, Parkinson's disease features a number of degenerative alterations, which often anticipate motor symptoms. Among these, the GI tract is often involved, and for this reason, it is important to assess its normal and pathological structure. A deeper knowledge of the ENS is expected to improve the understanding of diagnosis and treatment of Parkinson's disease.

Norepinephrine Protects against Methamphetamine Toxicity through ß2-Adrenergic Receptors Promoting LC3 Compartmentalization.

Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane ß2-adrenergic receptors (ARs). Evidence indicates that ß2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.

Neuroprotective Effects of Curcumin in Methamphetamine-Induced Toxicity.

Curcumin (CUR), a natural polyphenol extracted from rhizome of the Curcuma longa L, has received great attention for its multiple potential health benefits as well as disease prevention. For instance, CUR protects against toxic agents acting on the human body, including the nervous system. In detail, CUR possesses, among others, strong effects as an autophagy activator. The present study indicates that CUR counteracts methamphetamine (METH) toxicity. Such a drug of abuse is toxic by disturbing the autophagy machinery. We profited from an unbiased, low variable cell context by using rat pheochromocytoma PC12 cell line. In such a system, a strong protection was exerted by CUR against METH toxicity. This was associated with increased autophagy flux, merging of autophagosomes with lysosomes and replenishment of autophagy vacuoles with LC3, which instead is moved out from the vacuoles by METH. This is expected to enable the autophagy machinery. In fact, while in METH-treated cells the autophagy substrates α-synuclein accumulates in the cytosol, CUR speeds up α-synuclein clearance. Under the effects of CUR LC3 penetrate in autophagy vacuoles to commit them to cell clearance and promotes the autophagy flux. The present data provide evidence that CUR counteracts the neurotoxic effects induced by METH by promoting autophagy.

Chronic MPTP in Mice Damage-specific Neuronal Phenotypes within Dorsal Laminae of the Spinal Cord.

The neurotoxin 1-methyl, 4-phenyl, 1, 2, 3, 6-tetrahydropiridine (MPTP) is widely used to produce experimental parkinsonism. Such a disease is characterized by neuronal damage in multiple regions beyond the nigrostriatal pathway including the spinal cord. The neurotoxin MPTP damages spinal motor neurons. So far, in Parkinson's disease (PD) patients alpha-synuclein aggregates are described in the dorsal horn of the spinal cord. Nonetheless, no experimental investigation was carried out to document whether MPTP affects the sensory compartment of the spinal cord. Thus, in the present study, we investigated whether chronic exposure to small doses of MPTP (5 mg/kg/X2, daily, for 21 days) produces any pathological effect within dorsal spinal cord. This mild neurotoxic protocol produces a damage only to nigrostriatal dopamine (DA) axon terminals with no decrease in DA nigral neurons assessed by quantitative stereology. In these experimental conditions we documented a decrease in enkephalin-, calretinin-, calbindin D28K-, and parvalbumin-positive neurons within lamina I and II and the outer lamina III. Met-Enkephalin and substance P positive fibers are reduced in laminae I and II of chronically MPTP-treated mice. In contrast, as reported in PD patients, alpha-synuclein is markedly increased within spared neurons and fibers of lamina I and II after MPTP exposure. This is the first evidence that experimental parkinsonism produces the loss of specific neurons of the dorsal spinal cord, which are likely to be involved in sensory transmission and in pain modulation providing an experimental correlate for sensory and pain alterations in PD.

Locus Coeruleus Modulates Neuroinflammation in Parkinsonism and Dementia.

Locus Coeruleus (LC) is the main noradrenergic nucleus of the central nervous system, and its neurons widely innervate the whole brain. LC is severely degenerated both in Alzheimer's disease (AD) and in Parkinson's disease (PD), years before the onset of clinical symptoms, through mechanisms that differ among the two disorders. Several experimental studies have shown that noradrenaline modulates neuroinflammation, mainly by acting on microglia/astrocytes function. In the present review, after a brief introduction on the anatomy and physiology of LC, we provide an overview of experimental data supporting a pathogenetic role of LC degeneration in AD and PD. Then, we describe in detail experimental data, obtained in vitro and in vivo in animal models, which support a potential role of neuroinflammation in such a link, and the specific molecules (i.e., released cytokines, glial receptors, including pattern recognition receptors and others) whose expression is altered by LC degeneration and might play a key role in AD/PD pathogenesis. New imaging and biochemical tools have recently been developed in humans to estimate in vivo the integrity of LC, the degree of neuroinflammation, and pathology AD/PD biomarkers; it is auspicable that these will allow in the near future to test the existence of a link between LC-neuroinflammation and neurodegeneration directly in patients.

Cell Clearing Systems as Targets of Polyphenols in Viral Infections: Potential Implications for COVID-19 Pathogenesis.

The novel coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has generated the ongoing coronavirus disease-2019 (COVID-19) pandemic, still with an uncertain outcome. Besides pneumonia and acute lung injury (ALI) or acute respiratory distress syndrome (ARDS), other features became evident in the context of COVID-19. These includes endothelial and coagulation dysfunction with disseminated intravascular coagulation (DIC), and multiple organ dysfunction syndrome (MODS), along with the occurrence of neurological alterations. The multi-system nature of such viral infection is a witness to the exploitation and impairment of ubiquitous subcellular and metabolic pathways for the sake of its life-cycle, ranging from host cell invasion, replication, transmission, up to a cytopathic effect and overt systemic inflammation. In this frame, alterations in cell-clearing systems of the host are emerging as a hallmark in the pathogenesis of various respiratory viruses, including SARS-CoV-2. Indeed, exploitation of the autophagy and proteasome pathways might contribute not only to the replication of the virus at the site of infection but also to the spreading of either mature virions or inflammatory mediators at both cellular and multisystem levels. In this frame, besides a pharmacological therapy, many researchers are wondering if some non-pharmacological substances might counteract or positively modulate the course of the infection. The pharmacological properties of natural compounds have gained increasing attention in the field of alternative and adjunct therapeutic approaches to several diseases. In particular, several naturally-occurring herbal compounds (mostly polyphenols) are reported to produce widespread antiviral, anti-inflammatory, and anti-oxidant effects while acting as autophagy and (immuno)-proteasome modulators. This article attempts to bridge the perturbation of autophagy and proteasome pathways with the potentially beneficial effects of specific phytochemicals and flavonoids in viral infections, with a focus on the multisystem SARS-CoV-2 infection.

The Multi-Faceted Effect of Curcumin in Glioblastoma from Rescuing Cell Clearance to Autophagy-Independent Effects.

The present review focuses on the multi-faceted effects of curcumin on the neurobiology glioblastoma multiforme (GBM), with a special emphasis on autophagy (ATG)-dependent molecular pathways activated by such a natural polyphenol. This is consistent with the effects of curcumin in a variety of experimental models of neurodegeneration, where the molecular events partially overlap with GBM. In fact, curcumin broadly affects various signaling pathways, which are similarly affected in cell degeneration and cell differentiation. The antitumoral effects of curcumin include growth inhibition, cell cycle arrest, anti-migration and anti-invasion, as well as chemo- and radio-sensitizing activity. Remarkably, most of these effects rely on mammalian target of rapamycin (mTOR)-dependent ATG induction. In addition, curcumin targets undifferentiated and highly tumorigenic GBM cancer stem cells (GSCs). When rescuing ATG with curcumin, the tumorigenic feature of GSCs is suppressed, thus counteracting GBM establishment and growth. It is noteworthy that targeting GSCs may also help overcome therapeutic resistance and reduce tumor relapse, which may lead to a significant improvement of GBM prognosis. The present review focuses on the multi-faceted effects of curcumin on GBM neurobiology, which represents an extension to its neuroprotective efficacy.

Merging the Multi-Target Effects of Phytochemicals in Neurodegeneration: From Oxidative Stress to Protein Aggregation and Inflammation.

Wide experimental evidence has been provided in the last decade concerning the neuroprotective effects of phytochemicals in a variety of neurodegenerative disorders. Generally, the neuroprotective effects of bioactive compounds belonging to different phytochemical classes are attributed to antioxidant, anti-aggregation, and anti-inflammatory activity along with the restoration of mitochondrial homeostasis and targeting alterations of cell-clearing systems. Far from being independent, these multi-target effects represent interconnected events that are commonly implicated in the pathogenesis of most neurodegenerative diseases, independently of etiology, nosography, and the specific misfolded proteins being involved. Nonetheless, the increasing amount of data applying to a variety of neurodegenerative disorders joined with the multiple effects exerted by the wide variety of plant-derived neuroprotective agents may rather confound the reader. The present review is an attempt to provide a general guideline about the most relevant mechanisms through which naturally occurring agents may counteract neurodegeneration. With such an aim, we focus on some popular phytochemical classes and bioactive compounds as representative examples to design a sort of main highway aimed at deciphering the most relevant protective mechanisms which make phytochemicals potentially useful in counteracting neurodegeneration. In this frame, we emphasize the potential role of the cell-clearing machinery as a kernel in the antioxidant, anti-aggregation, anti-inflammatory, and mitochondrial protecting effects of phytochemicals.