Outline
Comptes Rendus

Neurosciences/Neurosciences
Altered nigrostriatal dopaminergic and noradrenergic system prompted by systemic lead toxicity versus a treatment by curcumin-III in the desert rodent Meriones shawi
Comptes Rendus. Biologies, Volume 342 (2019) no. 5-6, pp. 192-198.

Abstract

Exposure to lead is a threat factor for neurodegenerative disorders progress as it could trigger dopaminergic deficiency. We aimed herein to assess the effect of acute lead exposure (25 mg/kg B.W i.p.) during three continuous days on the dopaminergic and noradrenergic systems together with locomotor performance in Meriones shawi (M. shawi), then the neuroprotective potential of curcumin-III (30 mg/kg B.W) by oral gavage. Pb-exposed M. shawi exhibited increased tyrosine hydroxylase (TH) immunoreactivity in substantia nigra compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC), and dorsal striatum (DS), unlike the controls. This was correlated with decreased locomotor performance. A noticeable protective effect by co-treatment with curcumin-III was observed; in consequence, TH-immunoreactivity and locomotor disturbance were restored in Pb-treated Meriones. Our data results proved, on the one hand, an evident neurotoxic effect of acute Pb exposure and, on the other hand, a potent therapeutic effect of curcumin-III. Thereby, this compound may be recommended as a neuroprotective molecule for neurodegenerative disorders involving catecholaminergic impairment initiated by metallic elements.

Metadata
Received:
Accepted:
Published online:
DOI: 10.1016/j.crvi.2019.07.004
Keywords: Curcumin-III, Lead neurotoxicity, Midbrain, Dopamine and noradrenaline, Locomotion, Meriones shawi

Lahcen Tamegart 1; Abdellatif Abbaoui 1; Abdelaati El Khiat 1; Moulay Mustapha Bouyatas 1, 2; Halima Gamrani 1

1 Cadi Ayyad University, Faculty of Sciences Semlalia, Neurosciences, Pharmacology and Environment Unit, Avenue My Abdellah, B.P. 2390, Marrakech, Morocco
2 Cadi Ayyad University, Multidisciplinary Faculty of Safi, Department of Biology, Safi, Morocco
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     title = {Altered nigrostriatal dopaminergic and noradrenergic system prompted by systemic lead toxicity versus a treatment by {curcumin-III} in the desert rodent {\protect\emph{Meriones} shawi}},
     journal = {Comptes Rendus. Biologies},
     pages = {192--198},
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Lahcen Tamegart; Abdellatif Abbaoui; Abdelaati El Khiat; Moulay Mustapha Bouyatas; Halima Gamrani. Altered nigrostriatal dopaminergic and noradrenergic system prompted by systemic lead toxicity versus a treatment by curcumin-III in the desert rodent Meriones shawi. Comptes Rendus. Biologies, Volume 342 (2019) no. 5-6, pp. 192-198. doi : 10.1016/j.crvi.2019.07.004. https://comptes-rendus.academie-sciences.fr/biologies/articles/10.1016/j.crvi.2019.07.004/

Original version of the full text

1 Introduction

Systemic lead (Pb) toxicity induced many effects, while acute and prolonged systemic exposure to Pb affects several body systems, such as the gastrointestinal, hematopoietic, cardiovascular, nervous, immune, reproductive, and excretory systems [1,2]. Several data have shown that Pb is able to disturb different neurotransmitter system functions such as the GABAergic, cholinergic, adrenergic, glutaminergic, serotoninergic, dopaminergic, and peptidergic systems [3–9]. Other studies convincingly demonstrated the neurotoxic potential of Pb and suggested it as a menace for PD development [10–12]. Pb is able to act at different levels; thus, chronic exposure to Pb in drinking water diminished TH-expression within SNc and the motor cortex [13]. The disturbance of striatal and cerebellar functions due to the impaired catecholaminergic system [dopamine (DA) and noradrenaline (NA)] could be involved in hyperactivity and motor coordination problems, which were associated with prenatal Pb exposure [13,14]. Furthermore, Pb modulates the release of DA [15]; in fact, after weaning, exposure to 50 and 150 ppm of Pb acetate increased meaningfully DA released after the injection of KCl into the nucleus accumbens [16]. Also, the exposure to a low level of Pb decreases the DA liberation in the nucleus accumbens of rats [17]. In addition, it was revealed that lifetime exposure to lead induces oxidative stress in the rats brain [18]; also, Pb exposure could disrupt synaptic transmission, whereas a study shows that Pb-chronic exposure impairs in vivo generation of long-term potentiation in rat hippocampal dentate [19].

Curcumin, a major compound in the rhizome of Curcuma longa, is commonly used as a nutriment additive in Indian and Chinese traditional medicine [20]. It is also very popular in the kitchen and considered as an integral and ubiquitous spice [21]. Curcumin-III (bisdemethoxycurcumin, BDMC) is an antioxidant [22], a potential antimicrobial agent [23], a potent anti-inflammatory [24], antimutagenic [25], and an antitumor [26]. Valuable properties of BDMC were defined beside neurodegenerative diseases, especially PD [27].

However, the BDMC outcomes against lead-prompted Parkinsonism in rodents have never been clarified. Therefore, we aim in this investigation to evaluate the locomotor performance (vertical and horizontal locomotion) in Meriones acutely exposed to Pb, in parallel with the possible dopaminergic and noradrenergic dysfunctions within SNc, VTA and LC, then to evaluate the putative neuroprotective effect of BDMC.

2 Materials and methods

2.1 Animals

Four-month-old male Meriones, 200–250 g, delivered by the central animal-care facilities of Cadi Ayyad University, Marrakech (UCAM), Morocco, were retained at constant temperature (25 °C) on a 12-h dark–light cycle. All animals have ad libitum access to water and food. All Meriones treatments were completed with respect to the UCAM guidelines. All procedures were in accordance with the European Directive No. 2010/63/UE of 22 September 2010 (adapted into French law by the 2013-118 decree of 1st February 2013, related to the ethical evaluation and authorization of projects using animals for experimental procedures, NOR: AGRG1238767A). Therefore, all efforts were made to minimize the number of suffering animals.

Meriones were separated into four groups:

  • • group I: control Meriones (C) (n = 7) were injected intraperitoneally with a physiological saline buffer (NaCl, 9‰) for three consecutive days;
  • • group II: Meriones (Pb) (n = 7) received an intraperitoneal injection of Pb (25 mg/kg BW) dissolved in distilled water for three consecutive days;
  • • group III: Meriones (CurIII + Pb) (n = 7) pretreated with curcumin-III, dissolved in olive oil, at a dose of 30 mg/kg BW by oral gavage daily for three days. Animals of this group received an intraperitoneal injection with Pb (25 mg/kg BW) 2 h after they had been given the last dose of curcumin-III repeatedly for three days;
  • • group IV: Meriones (Cur III) (n = 7) were treated orally with curcumin-III, dissolved in olive oil, at a dose of 30 mg/kg B.W. daily for 3 days and were injected i.p. with a physiological saline buffer (0.9% NaCl).

2.2 Chemicals

Lead (II) acetate trihydrate was supplied by (Panreac Quimica S.L.U., Spain; code No. 2061044, lot No. 0000450930).

Curcumin-III: (1E,6E)-1,7-bis(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (C19H16O4) provided by Sigma-Aldrich Chemie GmbH, Germany ‘code No. B6938’.

2.3 Open-field test

This test was used to evaluate locomotor performance. The apparatus comprises 25 equal boxes of 20 cm per side (100 cm × 100 cm × 40 cm). Each Meriones was put in the center of the arena, then, the rearings (vertical locomotion) and the total crossed quadrangles (Horizontal locomotion) by each Meriones were checked during 5 min. Prior to the test, Meriones were given habituation periods for 10 min for three continual days [28].

2.4 Immunohistochemistry

After all experiments, Meriones were sacrificed 24 h after the last Pb-injection for the immunohistochemical investigation. Meriones were anesthetized using urethane (40 mg/kg i.p.), then, perfused transcardially with a cool physiological saline buffer (NaCl 0.9%) (Sigma-Aldrich, St. Louis, MO, USA) and paraformaldehyde (PFA) (4%) (Panreac Quimica SA, Barcelona, Spain) in a phosphate saline buffer (PBS, 0.1M, pH7.4) (Riedel-de Haen, Seelze, Germany). Afterward, brains were detached and post-fixed in PFA (4%) for 12 h at 4 °C, then dehydrated through a graded ethanol series (70–100%), passed via polyethylene glycol serial (Merck-Shuchardts, Hohenbrunn, Germany) (PEG: 40 to 100%) solutions and embedded in pure PEG. Coronal sections of 20 μm were made using a microtome according to the rat brain in stereotaxic coordinates and put in a phosphate saline buffer (PBS). Slices were chosen all over the midbrain, through substantia nigra compacta (SNc), ventral tegmental area (VTA) (bregma, 5.3 mm), locus coeruleus (LC) (bregma, 9.6 mm) and the dorsal striatum (bregma, 0.20 mm). The slices were preincubated for 2 h in PBS with 0.3% triton and 0.1% bovine serum albumin (BSA) (Sigma-Aldrich, St. Louis, USA) with agitation; then, they were incubated overnight at 4 °C in a solution of monoclonal TH antibody (Santa Cruz, CA, USA), diluted to 1:1000, comprising PBS (0.1 M, pH 7.4), Triton (0.3%), and BSA (1%). After that, the slices were washed three times by PBS (0.1 M, pH 7.4) during 5 min, before incubation with the secondary antibody (rabbit anti-immunoglobulins, 1/500) (Vector Labs, Burlingame, CA, USA) for 2 h at room temperature. Subsequently, the slices were washed three times and incubated for 2 h in a PBS buffer containing Triton (0.3%) and the avidin–biotin peroxidase complex (Kit ABC 1/500) (Vector Laboratories Burlingame, CA, USA). The revelation of TH-immunoreactivity was performed by the enzymatic reaction of peroxidase in the presence of the 3,3-diaminobenzidine (0.03%) (Sigma-Aldrich, Oakville, Canada) and hydrogen peroxide (0.006%) in Tris buffer (0.05 M pH 7.5). Next, the sections were dehydrated and mounted using Eukit for microscopy analysis and observation. The immunoreactive materials specificity was tested and revealed that the primary antibodies used against TH display specific labeling, as described in our previous studies [28–33].

2.5 Immunolabeling quantification

We performed the quantification of TH-immunoreactivity (TH-IR) in all brain structures, including substantia nigra compacta, ventral tegmental area, locus coeruleus, and dorsal striatum, using Vilaplana and Lavialle's protocol [34]. Images digitization and storage were realized using a Zeiss-Axioskop 40 microscope (Carl Zeiss; Oberkochen, Germany) and a mounted-Nikon digital camera. Images were digitized into 512 × 512 pixels with eight bits of gray resolution and were stored in TIFF format. Image processing and quantification were performed using Adobe Photoshop v.6.0 (Adobe Systems, San Jose, CA, USA). After conversion of each image to the binary mode, the percentages of black pixels were obtained using the image histogram option of Adobe Photoshop. This percentage corresponds to the TH-immunopositive area throughout the whole nucleus or the projections. Five sections from each animal of each group were randomly chosen for the quantification.

2.6 Statistical analysis

Our data were subjected to a one-way analysis of variance (ANOVA). Post-hoc differences between group means were tested with the Tukey test. Data are reported as mean ± S.E.M. and P-values < 0.05 were considered significant. Statistical analyses were performed using computer software SPSS 10.0 for Windows (SPSS, IBM, Chicago, IL, USA).

3 Results

3.1 Outcomes of acute Pb exposure and curcumin-III on locomotor performance

The acutely Pb-intoxicated animals, presented a severe decrease (P < 0.005) of the traversed quadrangles number (horizontal locomotion) and the same for the rearing number (vertical locomotion); such impairments implied an injury of locomotor performance in Pb-intoxicated Meriones (5 ± 0.57) compared to the controls (130 ± 1.7) (Fig. 1A and B). Co-treatment by curcumin-III improved (P < 0.005) the locomotor activity of Pb-treated Meriones (145 ± 1.45); however, no significant variation was proved by Meriones treated by curcumin-III (153 ± 1.7) alone (Fig. 1A and B), when compared to the control group.

Fig. 1

Histograms showing the number of crossed squares during observation in Meriones for 5 min using the open-field test (A; horizontal movement) and the number of rearings (B; vertical movement). C: control, Pb: Pb-treated, Cur + Pb: curcumin-III + Pb-treated, Cur: curcumin-III treated. Data are shown as group mean values ± S.E.M. ***P < 0.005 vs. controls and ### P < 0.005 vs. the Pb group.

3.2 Pb neurotoxicity and restorative potential of curcumin-III on altered nigrostriatal dopaminergic and noradrenergic system

An immunohistochemistry study was performed to assess TH-IRin SNc, VTA, LC and the dorsal striatum. A significant (P < 0.05) increase of TH-IR was observed in Pb-intoxicated Meriones, within SNc (52 ± 0.33) (Fig. 2B), VTA (24 ± 0.55) (Fig. 3B), LC (24 ± 0.88) (Fig. 5B), and the striatum (24 ± 0.66) (Fig. 4B). Both neurons and fibers in intoxicated Meriones were highly immunoreactive compared to controls (Fig. 2A and B). Oral gavage of curcumin-III to Pb-intoxicated Meriones seem to protected DAergic and noradrenergic innervations by restoring TH-IR within SNc and VTA nuclei (P < 0.05) (Figs. 2C, 3C and 5C), also within fibers in striatum (Fig. 4C). In fact, both cells and processes are clearly immunostained, whereas TH-immunoreactivity in Pb-treated Meriones was significantly (P < 0.05) repaired within SNc (25 ± 0.55), VTA (13 ± 0.5) (Figs. 2C, 3C), LC (12 ± 0.55) (Fig. 5C), and in the dorsal striatum (11 ± 0.57) (Fig. 5C). By contrast, curcumin-III alone induced a non-significant augmentation of TH-IR in comparison to the control group (Figs. 2D, 3D, 4D and 5D).

Fig. 2

Light micrographs of frontal sections through substantia nigra compacta (SNc) immunolabelled with antiserum against tyrosine hydroxylase (TH) in control (A), Pb-treated (B), Pb + Cur (C), Cur (D): a, b, c, d: high magnification of (SNc) in control, Pb-treated, Pb + Cur treated, and Cur treated, respectively. Data are shown as group means ± S.E.M. * P < 0.05 vs. controls; and # P < 0.05 vs. the Pb group.

Fig. 3

Light micrographs of frontal sections through ventral tegmental area (VTA) immunolabelled with antiserum against tyrosine hydroxylase (TH) in control (A), Pb-treated (B), Pb + Cur treated (C), Cur treated (D). Data are shown as group means ± S.E.M. * P < 0.05 vs. controls; and # P < 0.05 vs. the Pb group.

Fig. 5

Light micrographs of frontal sections through locus coeruleus (LC) immunolabelled with antiserum against tyrosine hydroxylase (TH) in control (A), Pb-treated (B), Pb + Cur treated (C), Cur treated (D). Data are shown as group means ± S.E.M. * P < 0.05 vs. controls; and # P < 0.05 vs. the Pb group.

Fig. 4

Light micrographs showing tyrosine hydroxylase (TH)-immunopositive fibers in the dorsal striatum of control (A), Pb-treated (B), Pb + Cur treated (C), Cur treated (D) Meriones. Data are shown as group means ± S.E.M. * P < 0.05 vs. controls; and # P < 0.05 vs. the Pb group.

4 Discussion

4.1 Pb intoxication increased TH-IR and locomotor activity

Our results showed that systemic Pb-toxicity increased TH-IR within SNc, VTA, and noradrenergic neurons in locus coeruleus as well as it increased TH-IR and density fibers within the striatum. These alterations may possibly be the cause of locomotor damages perceived in Pb-intoxicated Meriones. Studies support this finding; in fact, it has shown that prenatal exposure to Pb in rats at different ages induces synaptosomal increase of DA in the cerebellum, the hippocampus, and the cerebral cortex [3,35]. Similarly, chronic Pb post-weaning exposure (11 weeks and/or 11 months) showed increased DA in the nucleus accumbens [16]. Another study showed enhanced striatal DA release following systemic acute Pb intoxication at a dose of 6 g/kg [36]. Furthermore, maternal exposure to lead induces variations in the monoamine amount, with increases in dopamine and serotonin or their metabolites [5]. Activation of TH implicated calcium calmodulin-dependent phosphorylation; thus, studies have reported that lead increases calmodulin activity in the brain [37]. So, by competing with calcium, Pb is able to enhance TH activation [38].

We observed a diminution of locomotor performance in Pb-intoxicated Meriones, which is reliable to the neuromodulatory effect of dopamine in the nigro-cortico-striatal conduits in locomotor behavior [39]. Other studies support our data, revealing that systemic Pb disrupts locomotor activity, also, Pb-exposed mice at a dose of 100 mg/kg for two days decreased locomotor behavior [40]. In addition, the observed hypoactivity was described by other studies showing that exposure to Pb at a dose of 5 g/L for three months reduced significantly locomotor activity [13]. Some investigations have linked neurobehavioral impairments to the neurotoxic outcomes of Pb on the dopaminergic, cholinergic, and serotoninergic neurotransmitters systems. We suppose that Pb disturbs locomotion in Meriones by touching dopamine synthesis or its release [41]. Studies have shown that prenatal exposure to Pb, which causes alteration in locomotor activity revealed by the open-field, can be attributed to disturbances of the cholinergic system and aminergic systems (DA, NA) at the hippocampus [3,42]. It has also showed that other metal elements decreased locomotor performance, especially copper (Cu), by disturbing TH-expression [28–31].

4.2 Curcumin-III restored DAergic, noradrenergic, and locomotion deficit in Pb-intoxicated Meriones

Our study showed a neuroprotective potential of curcumin-III against DAergic neurotoxicity generated by Pb. Curcumin-III recovered TH-IRin SNc, VTA, LC and dorsal striatum, then improved the locomotor performance in Pb-intoxicated Meriones. Curcumin-III itself, compared to the control animals, shows a slight effect on horizontal locomotion, but several studies showed that the group treated only by curcumin did not demonstrate high significant change of locomotor activity [30], also in a rat model of postoperative pain; all the doses of curcumin did not expressively alter the spontaneous locomotor activity in a rat model of postoperative pain [43]. Furthermore, curcumin showed no significant effect on open-field locomotor activity [44]. This result is consistent with a previous study showing that curcuminoids [curcumin (CUR), demethoxycurcumin (DMC)], and BDMC provide significant protection against neuronal degeneration in nigrostriatal system damage in 6-OHDA-induced PD in Wistar rats [27]. This molecule has demonstrated a potent neuroprotective effect against lead-induced neurotoxicity in Wistar rats [45]. Furthermore, a study showed that curcuminoids provide neuroprotective effects against neurodegenerative disorders, while a standard extract of curcuminoids containing 78.1% of curcumin, 16.5% of demethoxycurcumin, and 5.4% of bisdemethoxycurcumin displayed a neuroprotective potential against inflammation-mediated dopaminergic neurodegeneration in the MPTP Model of PD [46]. However, studies showed that the protective effect of BDMC was not due to the central effect only, while BDMC have a strong systemic anti-inflammatory effect [24]. This neuroprotective effect of BDMC in the nigrostriatal system might be explained by many mechanisms. Some studies revealed an inhibitor effect of different curcuminoids on the β-amyloid protein, while BDMC could reduce the proteolysis of site APP cleaving enzyme 1 (BACE1) mRNA and protein levels in swAPP HEK293 cells; BDMC could be used for modulation of BACE1 and as a treatment of Alzheimer's disease (AD) [47]. Also, curcumin and its metabolite tetrahydrocurcumin have an inhibitory effect on MAO-B in the MPTP model of Parkinson's disease in mice [48]. A recent study described an inhibitor effect of curcumin on human MAO-A and MAO-B activity [49]; at that point, MAO-A and MAO-B are implicated in depression, PD, and AD [50,51]. In addition, an antioxidant power could be involved in the neuroprotective effect of curcumin-III. In fact, it has been shown that curcuminoids including BDMC have an antioxidant potential and may protect PC12 rats from pheochromocytoma [52]. Furthermore, BDMC defends against oxidative stress in rats [53]. Curcumin can also defend against ROS production via its antioxidant potential [54]. On the other hand, it prevents neurotoxicity through its scavenging capacity of metal elements [45], then improved locomotor performance in two animal models of copper-intoxication-induced locomotor deficiency [28,30].

5 Conclusion

Our study revealed an obvious neurotoxic consequence of Pb exposure on both the dopaminergic and noradrenergic systems together with locomotor activity disturbance. These toxic effects were restored by BDMC. As a result, curcumin-III could be used as a healing compound against Pb neurotoxicity, especially for DAergic and noradrenergic systems disorder.

Disclosure of interest

The authors declare that they have no competing interest.

Acknowledgements

Moroccan/Tunisian Action. Reference: M/T: 03/17.


References

[1] J. García-Lestón; J. Méndez; E. Pásaro; B. Laffon Genotoxic effects of lead: an updated review, Environ. Int., Volume 36 (2010), pp. 623-636

[2] K. Liu; J. Hao; Y. Zeng; F. Dai; P. Gu Neurotoxicity and biomarkers of lead exposure: a review, Chinese Med. Sci. J., Volume 28 (2013), pp. 178-188

[3] D.C. Basha; M.U. Rani; C.B. Devi; M.R. Kumar; G.R. Reddy Perinatal lead exposure alters postnatal cholinergic and aminergic system in rat brain: reversal effect of calcium co-administration, Int. J. Dev. Neurosci., Volume 30 (2012), pp. 343-350

[4] S.V. Kala; A.L. Jadhav Region-specific alterations in dopamine and serotonin metabolism in brains of rats exposed to low levels of lead, Neurotoxicology, Volume 16 (1995) no. 2, pp. 297-308

[5] M.L. Leret; F. Garcia-Uceda; M.T. Antonio Effects of maternal lead administration on monoaminergic, GABAergic and glutamatergic systems, Brain Res. Bull., Volume 58 (2002), pp. 469-473

[6] Z.D. Luo; H.A. Berman The influence of Pb2+ on expression of acetylcholinesterase and the acetylcholine receptor, Toxicol. Appl. Pharmacol., Volume 145 (1997), pp. 237-245

[7] D.J. Minnema; R.D. Greenland; I.A. Michaelson Effect of in vitro inorganic lead on dopamine release from superfused rat striatal synaptosomes, Toxicol. Appl. Pharmacol., Volume 82 (1986) no. 2, pp. 400-411 | DOI

[8] M.J. Pokora; E.K. Richfield; D.A. Cory-Slechta Preferential vulnerability of nucleus accumbens dopamine binding sites to low level lead exposure: time course of effects and interactions with chronic dopamine agonist treatments, J. Neurochem., Volume 67 (1996), pp. 1540-1550

[9] S. Raunio; H. Tähti Glutamate and calcium uptake in astrocytes after acute lead exposure, Chemosphere, Volume 44 (2001), pp. 355-359

[10] S. Dietzel; R. Eils; K. Sätzler; H. Bornfleth; A. Jauch; C. Cremer; T. Cremer Evidence against a looped structure of the inactive human X-chromosome territory, Exp. Cell Res., Volume 240 (1998), pp. 187-196

[11] S. Duckett; P. Galle; R. Kradin The relationship between Parkinson syndrome and vascular siderosis: an electron microprobe study, Ann. Neurol., Volume 2 (1977), pp. 225-229

[12] J.M. Gorell; C.C. Johnson; B.A. Rybicki; E.L. Peterson; G.X. Kortsha; G.G. Brown; R.J. Richardson Occupational exposure to manganese, copper, lead, iron, mercury and zinc and the risk of Parkinson's disease, Neurotoxicology, Volume 20 (1999), pp. 239-247

[13] W. Sansar; S. Ahboucha; H. Gamrani Chronic lead intoxication affects glial and neural systems and induces hypoactivity in adult rat, Acta Histochem., Volume 113 (2011), pp. 601-607

[14] M.D. Ris; K.N. Dietrich; P.A. Succop; O.G. Berger; R.L. Bornschein Early exposure to lead and neuropsychological outcome in adolescence, J. Int. Neuropsychol. Soc., Volume 10 (2004), pp. 261-270

[15] D.A. Cory-Slechta; D.J. O’Mara; B.J. Brockel Nucleus accumbens dopaminergic medication of fixed interval schedule-controlled behavior and its modulation by low level lead exposure, J. Pharmacol. Exp. Ther., Volume 286 (1998), pp. 794-805

[16] C.L. Zuch; D.J. O’Mara; D.A. Cory-Slechta Low level lead exposure selectively enhances dopamine overflow in nucleus accumbens: an in vivo electrochemistry time course assessment, Toxicol. Appl. Pharmacol., Volume 150 (1998), pp. 174-185

[17] S.V. Kala; A.L. Jadhav Low level lead exposure decreases in vivo release of dopamine in the rat nucleus accumbens: a microdialysis study, J. Neurochem., Volume 65 (1995), pp. 1631-1635

[18] C. Feng; S. Liu; F. Zhou; Y. Gao; Y. Li; G. Du; Y. Chen; H. Jiao; J. Feng; Y. Zhang Oxidative stress in the neurodegenerative brain following lifetime exposure to lead in rats: changes in lifespan profiles, Toxicology, Volume 411 (2019), pp. 101-109

[19] S.M. Lasley; J. Polan-Curtain; D.L. Armstrong Chronic exposure to environmental levels of lead impairs in vivo induction of long-term potentiation in rat hippocampal dentate, Brain Res., Volume 614 (1993), pp. 347-351

[20] A. González-Salazar; E. Molina-Jijón; F. Correa; G. Zarco-Márquez; M. Calderón-Oliver; E. Tapia; C. Zazueta; J. Pedraza-Chaverri Curcumin protects from cardiac reperfusion damage by attenuation of oxidant stress and mitochondrial dysfunction, Cardiovasc. Toxicol., Volume 11 (2011), p. 357

[21] J.S. Jurenka Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research, Altern. Med. Rev., Volume 14 (2009), pp. 141-153

[22] G.K. Jayaprakasha; L.J. Rao; K.K. Sakariah Antioxidant activities of curcumin, demethoxycurcumin and bisdemethoxycurcumin, Food Chem., Volume 98 (2006), pp. 720-724

[23] O. Lawhavinit; N. Kongkathip; B. Kongkathip Antimicrobial activity of curcuminoids from Curcuma longa L. on pathogenic bacteria of shrimp and chicken, Kasetsart J. Nat. Sci., Volume 44 (2010), pp. 364-371

[24] R.S. Ramsewak; D.L. DeWitt; M.G. Nair Cytotoxicity, antioxidant and anti-inflammatory activities of curcumins I–III from Curcuma longa, Phytomedicine, Volume 7 (2000), pp. 303-308

[25] I.P. Kaur Antimutagenicity of curcumin and related compounds against genotoxic heterocyclic amines from cooked food: the structural requirement, Food Chem., Volume 111 (2008), pp. 573-579

[26] J.-L. Jiang; X.-L. Jin; H. Zhang; X. Su; B. Qiao; Y.-J. Yuan Identification of antitumor constituents in curcuminoids from Curcuma longa L. based on the composition–activity relationship, J. Pharm. Biomed. Anal., Volume 70 (2012), pp. 664-670

[27] S.S. Agrawal; S. Gullaiya; V. Dubey; V. Singh; A. Kumar; A. Nagar; P. Tiwari Neurodegenerative shielding by curcumin and its derivatives on brain lesions induced by 6-OHDA model of Parkinson's disease in albino wistar rats, Cardiovasc. Psychiatry Neurol., Volume 2012 (2012), p. 8

[28] A. Abbaoui; H. Gamrani Neuronal, astroglial and locomotor injuries in subchronic copper intoxicated rats are repaired by curcumin: a possible link with Parkinson's disease, Acta Histochem., Volume 120 (2018), pp. 542-550

[29] A. Abbaoui; H. Chatoui; O. El Hiba; H. Gamrani Neuroprotective effect of curcumin-I in copper-induced dopaminergic neurotoxicity in rats: a possible link with Parkinson's disease, Neurosci. Lett., Volume 660 (2017), pp. 103-108 | DOI

[30] A. Abbaoui; O. El Hiba; H. Gamrani Neuroprotective potential of Aloe arborescens against copper-induced neurobehavioral features of Parkinson's disease in rat, Acta Histochem., Volume 119 (2017), pp. 592-601 | DOI

[31] A. Abdellatif; E.L.H. Omar; G. Halima The neuronal basis of copper-induced modulation of anxiety state in rat, Acta Histochem., Volume 119 (2017), pp. 10-17 | DOI

[32] A. Abbaoui; O. El Hiba; H. Gamrani Copper poisoning induces neurobehavioral features of Parkinson's disease in rat: alters dopaminergic system and locomotor performance, Parkinsonism Relat. Disord., Volume 22 (2016), p. e188 | DOI

[33] L. Tamegart; A. Abbaoui; R. Makbal; M. Zroudi; B. Bouizgarne; M.M. Bouyatas; H. Gamrani Crocus sativus restores dopaminergic and noradrenergic damages induced by lead in Meriones shawi: a possible link with Parkinson's disease, Acta Histochem., Volume 121 (2018) no. 2, pp. 171-181

[34] J. Vilaplana; M. Lavialle A method to quantify glial fibrillary acidic protein immunoreactivity on the suprachiasmatic nucleus, J. Neurosci. Methods, Volume 88 (1999), pp. 181-187

[35] C.D. Basha; R.G. Reddy Long-term changes in brain cholinergic system and behavior in rats following gestational exposure to lead: protective effect of calcium supplement, Interdiscip. Toxicol., Volume 8 (2015), pp. 159-168

[36] H. Komulainen; R. Pietarinen; J. Tuomisto Increase in dopamine uptake in rat striatal synaptosomes after an acute in vivo administration of organic and inorganic lead, Acta Pharmacol. Toxicol. (Copenh)., Volume 52 (1983), pp. 381-389

[37] R. Sandhir; D. Julka; K. Dip Gill Lipoperoxidative damage on lead exposure in rat brain and its implications on membrane bound enzymes, Pharmacol. Toxicol., Volume 74 (1994), pp. 66-71

[38] P.J. Vig; R. Nath In vivo effects of cadmium on calmodulin and calmodulin regulated enzymes in rat brain, Biochem. Int., Volume 23 (1991), pp. 927-934

[39] L. Bonilla-Ramirez; M. Jimenez-Del-Rio; C. Velez-Pardo Acute and chronic metal exposure impairs locomotion activity in Drosophila melanogaster: a model to study Parkinsonism, Biometals, Volume 24 (2011), pp. 1045-1057

[40] M. Correa; A.F. Roig-Navarro; C.M.G. Aragon Motor behavior and brain enzymatic changes after acute lead intoxication on different strains of mice, Life Sci., Volume 74 (2004), pp. 2009-2021

[41] A.G. Molloy; J.L. Waddington Dopaminergic behaviour stereospecifically promoted by the D 1 agonist R-SK & F 38393 and selectively blocked by the D 1 antagonist SCH 23390, Psychopharmacology (Berl.), Volume 82 (1984), pp. 409-410

[42] D.C. Basha; N.S. Reddy; M.U. Rani; G.R. Reddy Age related changes in aminergic system and behavior following lead exposure: protection with essential metal supplements, Neurosci. Res., Volume 78 (2014), pp. 81-89

[43] Q. Zhu; Y. Sun; X. Yun; Y. Ou; W. Zhang; J.-X. Li Antinociceptive effects of curcumin in a rat model of postoperative pain, Sci. Rep., Volume 4 (2014), p. 4932

[44] L.L. Hurley; L. Akinfiresoye; E. Nwulia; A. Kamiya; A.A. Kulkarni; Y. Tizabi Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF, Behav. Brain Res., Volume 239 (2013), pp. 27-30

[45] A. Dairam; J.L. Limson; G.M. Watkins; E. Antunes; S. Daya Curcuminoids, curcumin, and demethoxycurcumin reduce lead-induced memory deficits in male Wistar rats, J. Agric. Food Chem., Volume 55 (2007), pp. 1039-1044

[46] R.P. Ojha; M. Rastogi; B.P. Devi; A. Agrawal; G.P. Dubey Neuroprotective effect of curcuminoids against inflammation-mediated dopaminergic neurodegeneration in the MPTP model of Parkinson's disease, J. Neuroimmune Pharmacol., Volume 7 (2012), pp. 609-618

[47] H. Liu; Z. Li; D. Qiu; Q. Gu; Q. Lei; L. Mao The inhibitory effects of different curcuminoids on β-amyloid protein, β-amyloid precursor protein and β-site amyloid precursor protein cleaving enzyme 1 in swAPP HEK293 cells, Neurosci. Lett., Volume 485 (2010), pp. 83-88

[48] A. Rajeswari; M. Sabesan Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model of Parkinson's disease induced by MPTP neurodegeneration in mice, Inflammopharmacology, Volume 16 (2008), pp. 96-99

[49] S.C. Baek; B. Choi; S.-J. Nam; H. Kim Inhibition of monoamine oxidase A and B by demethoxycurcumin and bisdemethoxycurcumin, J. Appl. Biol. Chem., Volume 61 (2018), pp. 10-13 | DOI

[50] Z. Fišar Drugs related to monoamine oxidase activity, Prog. Neuropsychopharmacol. Biol. Psychiatry, Volume 69 (2016), pp. 112-124

[51] R. Ramsay; K. Tipton Assessment of enzyme inhibition: a review with examples from the development of monoamine oxidase and cholinesterase inhibitory drugs, Molecules, Volume 22 (2017), p. 1192

[52] D.S.H.L. Kim; S.-Y. Park; J.-Y. Kim Curcuminoids from Curcuma longa L. (Zingiberaceae) that protect PC12 rat pheochromocytoma and normal human umbilical vein endothelial cells from βA (1-42) insult, Neurosci. Lett., Volume 303 (2001), pp. 57-61

[53] N. Ahmad; S. Umar; M. Ashafaq; M. Akhtar; Z. Iqbal; M. Samim; F.J. Ahmad A comparative study of PNIPAM nanoparticles of curcumin, demethoxycurcumin, and bisdemethoxycurcumin and their effects on oxidative stress markers in experimental stroke, Protoplasma, Volume 250 (2013), pp. 1327-1338

[54] Y.-B. Li; J.-L. Gao; Z.-F. Zhong; P.-M. Hoi; S.M.-Y. Lee; Y.-T. Wang Bisdemethoxycurcumin suppresses MCF-7 cells proliferation by inducing ROS accumulation and modulating senescence-related pathways, Pharmacol. Rep., Volume 65 (2013), pp. 700-709


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