A State Of The Art Of Antioxidant Properties Of Curcuminoids in Neurodegenerative Diseases Part 4
May 28, 2024
Although curcumin has excellent therapeutic potential against AD, its poor bioavailability and biodistribution could reduce its effectiveness. In this context, Fidelis et al. evaluated antioxidant and antidepressant effects using curcumin-loaded lipid core capsules (NLC C) in Swiss male mice reproducing AD models.
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To induce the AD model, aggregated acetyl Aβ25–35 (3 nmol/3µL) was administered intracerebroventricularly. Curcumin was administrated via intragastrical, to overcome its low bioavailability.
The mice were pre-treated with NLC C (10 mg/kg) every 48 h for 12 days. The results of the present study showed that NLC C reduced the levels of ROS and regularized the levels of antioxidant enzymes such as SOD and CAT raised by treatment with Aβ25–35 in the prefrontal cortex. However, studies carried out on the hippocampus did not reveal significant differences, but NCL C resulted in an increase in the SOD/CAT ratio.
Therefore, NLC C proved to be an effective treatment against oxidative stress induced by Aβ25–35 in the prefrontal cortex and also proved effective in attenuating the depressive behavior induced by Aβ25–35 infusion [97]. Also, Malvajerd et al. evaluated the effects of NLC C in male Sprague-Dawley rats Aβ1–42-treated to induce a model of AD.
The treatment of NLC C (4 mg/kg) administered intracerebroventricularly showed an overall reduction in the oxidative stress induced by the Aβ1–42 treatment in the hippocampal tissue of rats. Specifically, the results showed a decrease in MDA, ROS levels, and lipid peroxidation in the hippocampal tissue, demonstrating that curcumin counteracts oxidative stress.
Moreover, the researchers found an increase in thiols, peculiar to their antioxidant properties. A significant finding, the ADP/ATP ratio was also assessed, it was decreased in NLC C treatment compared to the sham group.
The efficacy of NLC C for brain delivery of curcumin was also confirmed by the improvement of spatial memory in rats. This evidence confirmed the antioxidant properties of curcumin and proved that NLC C is a good vector for reaching optimal concentrations in the brain [111].
5.3. Antioxidant Effects of Curcumin in Clinical Trial
Some clinical studies were conducted to investigate the potential effects of the efficacy of CBD in the management of AD. A group of Chinese researchers performed a phase 1/2 trial (NCT00164749), to evaluate the efficacy of curcumin in slowing the progression of AD.
In this study, 36 patients (50 years and older) with a progressive decline in cognitive function and memory for at least six months were enrolled. Patients were treated with a placebo or with 1 or 4 g of curcumin per day.
Additionally, all patients were treated with 120 mg of ginkgo extract per day. All participants were monitored at baseline, 1, 3, and 6 months after treatment. The primary outcome of the study was to assess the safety of curcumin to be able to design a larger study to test curcumin against AD.
The secondary objective of the study was to establish the biochemical mechanism used from curcumin and explain which of the two doses was more effective. Therefore, to assess whether curcumin could reduce levels of Aβ and oxidative stress-related proteins, blood samples were analyzed to measure levels of isoprostane, Aβ protein, metals, and cholesterol.
Cognitive tests were performed to evaluate the effects of curcumin on cognitive impairments typical of AD. In conclusion, the results of this study will help us understand whether curcumin can be used as a treatment to delay the progression of AD. The complete phase 2 study (NCT00099710), double-blind, aimed to evaluate the safety and tolerability of two doses of Curcumin C3 Complex ® in patients with mild or moderate AD.
The study enrolled 33 patients (50 years and older) randomized to receive one of two doses of oral curcumin (2 or 4 mg), or a placebo, for the first six months of the study.
After six months, patients in the placebo group received one of two doses of curcumin, thereby extending the study to another six months. Participants achieved seven visits during the 12-month study. Physical and neurological examinations, routine laboratory tests, and neuropsychological assessments were performed during these visits.
Specifically, the Alzheimer's Disease Assessment Scale, cognitive sub-portion (ADAS-Cog), the Neuropsychiatric Inventory (NPI) tool, and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) were used to assess the clinical outcomes of the treatment. Blood and cerebrospinal fluid tests were also done to assess how curcumin is absorbed by the body and its possible antioxidant and anti-inflammatory effects.
Part of the study results were published in the study conducted by Ringman J. M. et al. In this study, the authors reported only efficacy data at 6 months post-treatment and tolerability measures of curcumin up to 12 months.
After one year of treatment, curcumin was well tolerated; of the 33 patients enrolled, only three subjects withdrew from the study due to severe gastrointestinal symptoms. However, the study results did not report clinical data on the efficacy of curcumin against AD. Indeed, there were no significant differences between the treatment groups in ADAS-Cog, NPI, and ADCS-ADL scores.
There were also no significant changes in plasma and cerebrospinal fluid levels of Aβ1–40, Aβ1–42, tau, and p-tau. Additionally, curcumin appears to have shown low bioavailability.
In conclusion, the poor bioavailability, the lack of clinical data demonstrating the efficacy of curcumin in AD, and the partial publication of the data, do not allow definitive conclusions to be drawn from this study, further observations and long-term clinical studies will be necessary to understand the mechanisms used by curcumin to exert its beneficial effects.
Due to the poor bioavailability of curcumin, which does not allow for positive results in clinical studies, a phase 2 clinical trial (NCT01001637) was designed to determine the efficacy and safety of the highly bioavailable curcumin, solid-lipid curcumin particle (SLCP or Longvida). The study enrolled 26 participants (50 to 80 Years) with moderate or severe AD.
The patients were randomly divided into a group that received a placebo and a group treated with oral curcumin formulation at a dose of 2000 mg or 3000 mg daily. The primary outcome of the study was to evaluate the efficacy of curcumin formulation on the mental abilities of AD patients 2 months after treatment. The trial also aimed to evaluate changes in serum Aβ concentrations.
The results of the study have not yet been published, however, they will help to understand the oral dosing of curcumin solid-lipid particles and to evaluate its safety. Furthermore, data will be helpful in understanding whether formulated curcumin induces improvements in memory deficits and influences biomarkers of AD better than non-formulated curcumin.
In conclusion, preclinical findings demonstrated that curcuminoids during pre-treatment inhibit the Aβ aggregation, attenuate the tau hyperphosphorylation and, consequently, improve cognitive function and prevent the development of dementia (Table 2).
However, clinical studies that reveal the efficacy of curcuminoid treatment in AD patients with mild or moderate stages of the disease are few. Thus, further studies will be needed to encourage the use of curcuminoids as valid therapeutic tools in the management of AD.
6. Amyotrophic Lateral Sclerosis
ALS is a neurodegenerative disease characterized by progressive degeneration of both upper and lower motor neurons, resulting in muscle atrophy, and gradual paralysis that generally results in respiratory failure [112].
Respiratory failure usually occurs within 2–5 years of diagnosis due to respiratory muscle involvement. Furthermore, about 50% of ALS patients show evidence of frontal and temporal lobe dysfunction, while about 15% of patients with ALS, show some degree of motor involvement [113]. About 10% of patients with ALS follow a family pattern, mostly autosomal dominant (familial ALS), while 90% show a genetic basis (sporadic ALS).
Several gene mutations linked to ALS have been associated to date, including superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP43), and fused in sarcoma/translocated in sarcoma (FUS) genes.
The etiology of ALS remains completely misunderstood, however, like other neurodegenerative diseases, it is a multifactorial pathology [114]. Certainly, glutamate-induced excitotoxicity, microglia activation, apoptosis, neuroinflammation, oxidative stress, and mitochondrial dysfunction are all factors that play a key role in the pathogenesis of this disease [115,116].
Several studies have demonstrated the important role that oxidative stress plays a key role in the development and progression of ALS. Indeed, oxidative damage due to ROS accumulation has been confirmed in NSC-34 cells expressing mutant or wild-type TDP-43 genes [117].
Oxidative stress is responsible for alterations in redox signaling that exacerbate other pathophysiological processes such as excitotoxicity [118], mitochondrial damage [119], alterations in astrocyte and microglia signaling [120,121], responsible for damage to motor neurons. Treatment with antioxidant compounds may slow the progression of the disease in animal models of ALS [122,123].
Curcumin, in motor neuron cell lines transfected with the TDP-43 mutant, reduces oxidative stress and protects cells from mitochondrial damage [124,125]. Furthermore, curcumin activates Nrf2 target genes in primary astrocytes of the spinal cord. Since Nrf2 is a regulator of antioxidant genes, the activation of this antioxidant pathway may be a valid therapeutic strategy used by curcumin to prevent the loss of motor neurons in the spinal cord [126].
In this regard, Chico L. et al. evaluated the effects of curcumin in patients with ALS. Patients were randomized into two groups, one group received a placebo for three months and subsequently received oral curcumin (600 mg/day, Brainoil), for three months. While a second group was treated with curcumin for six months (600 mg/day, Brainoil).
Evaluations were performed at baseline after three months and after six months. Clinical evaluations were performed and biomarkers of oxidative stress were measured, including oxidative protein products (AOPP), ferric reducing capacity (FRAP), total thiols (T-SH), and lactate which were compared with a control group.
Throughout the entire study, the group that received curcumin from the outset showed a stable Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) score. Furthermore, this group always showed a reduction in AOPP (p < 0.01), which was not observed in group A. Curcumin administered for six months also maintained stable FRAP and decreased lactate.
Furthermore, the patients with ALS recruited in the study showed an increase in oxidative stress compared to healthy subjects. However, treatment with curcumin reduced oxidative stress. Thus oral supplementation of curcumin revealed encouraging data indicating a slight slowdown in disease progression, ameliorating aerobic metabolism, and reducing oxidative damage [127].
The effects of curcumin are also being evaluated in another clinical trial still under study. The ongoing trial registered in ClinicalTrials.gov (accessed on 12 February 2021) (NCT04654689), intends to evaluate the effects of curcumin used in combination with another polyphenol, resveratrol. The study recruited 100 ALS patients (over 18 years of age) for at least 6 months and were randomized into two groups.
One group will receive a single daily dose of the combination of resveratrol (75 mg) and curcumin (200 mg) liposomes with dutasteride for 6 months. The second group will receive a placebo at the same dose and for the same time frame. The placebo will consist of sucrose as a replacement for liposomal polyphenols, and a soft capsule of microcrystalline methylcellulose, instead of Dutasteride.
During the study, assessments will be performed at baseline, three months, and six months after treatment. Patients will undergo clinical evaluations using functional, cognitive, and behavioral tests through ALSFRS-R, electromyography, and measurement of forced vital capacity evaluations. Furthermore, to evaluate the possible antioxidant and anti-inflammatory effects induced by the treatment, quantitative plasma measurements of inflammatory cytokines such as plasma IL-6 and TNF-α and of oxidative stress markers such as Trolox Equivalent Antioxidant Capacity (TEAC), 8-oxoguanine and MDA.
The choice of using these compounds in liposomes or nanoparticles increases their stability, bioavailability, and absorption of the antioxidant. Indeed, the use of nanobiotechnology with curcumin (80 mg/day) in the treatment of patients with ALS has obtained positive outcomes demonstrating that nanocurcumin is safe and could improve the course of the disease, as well as proving to be a valid therapeutic strategy to use as an adjunct treatment in patients with ALS [128].
Therefore, the results of this clinical study will be useful in understanding the mechanisms by which these compounds exert their protective effects. Additionally, it will also be necessary to assess if natural compounds such as curcumin could be a valid therapeutic strategy to use in patients with ALS. These results suggest that curcuminoids, through their antioxidant effects, can prevent the loss of motor neurons.
Interestingly, the treatment of ALS patients with curcumin is safe and useful in improving and preventing the progression of the disease. Therefore, these data encourage the use of curcuminoids as a therapeutic strategy in the treatment of ALS.
7. Conclusions
This review summarized the studies that evaluate the antioxidant properties of curcuminoids related to their potential neuroprotective effects. Specifically, curcuminoids highlight powerful antioxidant actions through the activation of the Akt/Nrf2 pathway (Figure 3). Several preclinical studies have shown that curcuminoids possess therapeutic efficacy against AD, PD, and ALS. However, there are no available clinical studies for PD. Instead, few clinical trials are recorded concerning AD and ALS and limited results reported the efficacy and safety of curcuminoids. Therefore, clinical studies are needed to include curcuminoids in clinical practice.
Author Contributions: Conceptualization, E.M., and P.B.; writing-original draft preparation, S.S. and C.S.; writing-review and editing, E.M.; supervision, E.M.; funding acquisition, P.B. All authors have read and agreed to the published version of the manuscript.
Funding: This study was supported by Current Research Funds 2020, Ministry of Health, Italy.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: No new data were created or analyzed in this study. Data sharing does not apply to this article.
Acknowledgments: The authors would like to thank the Ministry of Health, Italy.
Conflicts of Interest: The authors declare no conflict of interest.
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