The Possible Neuroprotective Effect of Silymarin against Aluminum Chloride-Prompted Alzheimer's-Like Disease in Rats

Hanaa R Aboelwafa, Attalla F El-Kott, Eman M Abd-Ella, Hany N Yousef, Hanaa R Aboelwafa, Attalla F El-Kott, Eman M Abd-Ella, Hany N Yousef

Abstract

Alzheimer's disease (AD) is a worldwide rapidly growing neurodegenerative disease. Here, we elucidated the neuroprotective effects of silymarin (SM) on the hippocampal tissues of aluminum chloride (AlCl3)-induced Alzheimer-like disease in rats using biochemical, histological, and ultrastructural approaches. Forty rats were divided into control, SM, AlCl3, and AlCl3 + SM groups. Biochemically, AlCl3 administration resulted in marked elevation in levels of lipid peroxidation (LPO) and nitric oxide (NO) and decrease in levels of reduced glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Moreover, AlCl3 significantly increased tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), and acetylcholinesterase (AChE) activities. Furthermore, myriad histological and ultrastructural alterations were recorded in the hippocampal tissues of AlCl3-treated rats represented as marked degenerative changes of pyramidal neurons, astrocytes, and oligodendrocytes. Additionally, some myelinated nerve fibers exhibited irregular arrangement of their myelin coats, while the others revealed focal degranulation of their myelin sheaths. Severe defects in the blood-brain barrier (BBB) were also recorded. However, co-administration of SM with AlCl3 reversed most of the biochemical, histological, and ultrastructural changes triggered by AlCl3 in rats. The results of the current study indicate that SM can potentially mend most of the previously evoked neuronal damage in the hippocampal tissues of AlCl3-kindled rats.

Keywords: Alzheimer’s disease; aluminum chloride; hippocampus; histology; oxidative stress; silymarin; ultrastructure.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Levels of (a) malondialdehyde (MDA), (b) nitric oxide (NO) and (c) reduced glutathione (GSH), and activities of (d) superoxide dismutase (SOD) and (e) catalase (CAT) in hippocampal tissues of control and experimental groups of rats. Values are expressed as mean ± standard error of mean (SEM) (n = 6). Comparisons are as follows: * p ≤ 0.05, significantly different from Control; # p ≤ 0.05, significantly different from silymarin (SM); + p ≤ 0.05, AlCl3 significantly different from AlCl3 + SM group.
Figure 1
Figure 1
Levels of (a) malondialdehyde (MDA), (b) nitric oxide (NO) and (c) reduced glutathione (GSH), and activities of (d) superoxide dismutase (SOD) and (e) catalase (CAT) in hippocampal tissues of control and experimental groups of rats. Values are expressed as mean ± standard error of mean (SEM) (n = 6). Comparisons are as follows: * p ≤ 0.05, significantly different from Control; # p ≤ 0.05, significantly different from silymarin (SM); + p ≤ 0.05, AlCl3 significantly different from AlCl3 + SM group.
Figure 2
Figure 2
Levels of the proinflammatory cytokines (a) tumor necrosis factor-alpha (TNF-α) and (b) interleukin-1beta (IL-1β) in hippocampal tissues of control and experimental groups of rats. Values are expressed as mean ± SEM (n = 6). Comparisons are as follows: * p ≤ 0.05, significantly different from Control; # p ≤ 0.05, significantly different from SM; + p ≤ 0.05, AlCl3 significantly different from AlCl3 + SM group.
Figure 3
Figure 3
Levels of acetylcholinesterase (AChE) in hippocampal tissues of control and experimental groups of rats. Values are expressed as mean ± SEM (n = 6). Comparisons are as follows: * p ≤ 0.05, significantly different from Control; # p ≤ 0.05, significantly different from SM; + p ≤ 0.05, AlCl3 significantly different from AlCl3 + SM group.
Figure 4
Figure 4
Photomicrographs of the hippocampal tissues of control (a–d) and SM-treated rats (e–h) stained with Hx&E showing (a,e) normal structure of cornu ammonis (CA), dentate gyrus (DG), and subiculum (S). CA is formed of the pyramidale layer (PyL) merged between the molecular layer (ML) and polymorphic layer (PL). CA1, CA2, CA3, and CA4 are subfields of the stratum pyramidale. The DG is seen surrounding CA4 by its upper and lower limbs and forming of molecular (ML), granular (GL), and polymorphic (PL) layers; (b,f) small pyramidal cells (PC) of the CA1 subfield appeared with large vesicular nuclei. Glial cells (GC) and blood capillaries (BC) are noticed in the molecular (ML) and polymorphic (PL) layers; (c,g) large pyramidal cells (PC) of CA3 region, most with vesicular nuclei. Additionally, glial cells (GC) and blood capillaries (BC) are seen; (d,h) compact closely packed granular cells (G) with dark stained nuclei are seen in the granular layer of the DG. Blood capillaries (BC) and glial cells (GC) are noticed in the molecular (ML) and polymorphic (PL) layers.
Figure 5
Figure 5
Photomicrographs of the hippocampal tissues of AlCl3-treated rats stained with Hx&E showing (a) disruption of normal laminar organization, where the hippocampus appeared flattened, formed of CA1, CA2, CA3, and CA4 subfields, DG, and subiculum (S); (b) the CA1 subfield had disorganized small pyramidal cells (PC) and some of them appeared shrunken with pyknotic nuclei (→). Some glial cells (GC) appeared enlarged in the molecular (ML) and polymorphic (PL) layers; (c) another CA1 zone revealed marked shrunken small pyramidal cells (PC) and some of them showed pyknosis (→). Dilated congested blood capillaries (BC) and glial cells (GC) were also seen; (d) the CA3 subfield revealed large pyramidal cells (PC) exhibiting shrinkage with pyknotic nuclei, moreover, enlarged glial cells (GC) and dilated blood capillaries (BC) were noticed; (e) disorganized large pyramidal cells (PC) having pyknotic nuclei, in addition to fibrosis (F) were clearly seen in the surrounding neuropil in another CA3 area; (f) the granular cell layer (G) of the DG showed marked vacuolation (V). Molecular (ML) and polymorphic (PL) layers showed marked enlarged glial cells (GC).
Figure 6
Figure 6
Photomicrographs of the hippocampal tissues of AlCl3 + SM-treated rats stained with Hx&E showing (a) restoration of the laminar organization with preservation of the characteristic structure of the hippocampal tissues: CA1, CA2, CA3, and CA4, DG, and subiculum (S); (b) preservation of small pyramidal cells (PC) of the CA1 subfield with normal glial cells (GC) and blood capillaries (BC) in the molecular (ML) and polymorphic (PL) layers; (c) the CA3 subfield appeared with nearly normal large pyramidal cells (PC) having vesicular nuclei, additionally intact glial cells (GC) and blood capillaries (BC) were seen; (d) another CA3 area revealed large pyramidal cells (→) having dark nuclei among normal ones (PC); (e) preservation of normal organization of granular cells (G) of the DG with normal glial cells (GC) in both polymorphic (PL) and molecular (ML) layers.
Figure 7
Figure 7
Electron micrographs of the hippocampal CA1 subfields of control (a–d) and SM-treated rats (e–h) showing (a,e) pyramidal neurons possessing huge irregular nuclei (N) with dispersed chromatin and prominent nucleoli (Nu). Their cytoplasm appeared rich in rough endoplasmic reticulum (rER), mitochondria (M) with normal densities, and Golgi apparatus (GA). Moreover, the axon hillock (H) and its initial part with normal distribution of neurofilaments (F) and intact surrounding neuropil (NP) are clearly noticed; (b,f) astrocytes (A) containing irregular electron-dense nuclei and cytoplasm having few rER, Golgi apparatus (GA), and mitochondria (M), in addition to cytoplasmic extensions (C) can be identified. Furthermore, adjacent neuropil (NP) containing normal myelinated (MF) and non-myelinated (NF) fibers is observed; (c,g) oligodendrocytes (O) having electron-dense ovoid nuclei (N) and cytoplasm with rER and Golgi apparatus (GA), in addition to cytoplasmic extensions (C) are seen. The surrounding neuropil (NP) comprising some myelinated (MF) and non-myelinated (NF) axons is also observed; (d,h) numerous myelinated (MF) nerve fibers with regular myelin sheaths (←) or non-myelinated (NF) nerve fibers are seen in the neuropil (NP).
Figure 8
Figure 8
Electron micrographs of the hippocampal CA1 subfields of AlCl3-treated rats showing (a) a pyramidal nerve cell with irregular-shaped dispersed nucleus (N) and deformed cytoplasm illustrating dilated rER, swollen Golgi apparatus (GA), electron-dense mitochondria (M), and cytoplasmic vacuoles (V); (b) another distorted neuron with irregular shrunken nucleus (N), swollen cisternae of rER, swollen mitochondria (M) with their cristae partly missing, dilated Golgi apparatus (GA), lysosomes (Ly), and cytoplasmic vacuolation (V); (c) a severe degenerated neuron appeared with small heterochromatic nucleus (N) and vacuolated cytoplasm (*) with cytoplasmic remnants; (d) a deteriorated astrocyte (A) appeared with highly wrinkled nucleus (N) and cytoplasmic vacuolation (V). The surrounding neuropil (NP) revealed vacuolation (V), and myelinated nerve fibers (MF) with discontinuity of their myelin coats (←) are also seen; (e) two oligodendrocytes lying adjacent to the pyramidal nerve cell (PC) with one of them appearing pyknotic (PO) and the other one (O) possessing a small electron-dense nucleus (N). Furthermore, myelinated nerve fibers (MF) with discontinuity of their myelin coats (←) are seen in the neuropil (NP); (f) aggregated myelinated nerve fibers (MF) having abnormal or irregular thickened and arranged myelin sheaths (←), in addition to irregular non-myelinated nerve axons (NF) are clearly seen in the neuropil (NP).
Figure 9
Figure 9
Electron micrographs of the hippocampal CA1 subfields of AlCl3 + SM-treated rats showing (a) nearly normal pyramidal nerve cell which possesses irregular nucleus (N) with dispersed chromatin and the cytoplasm containing less electron-dense mitochondria (M), rER, and Golgi apparatus (GA); (b) an astrocyte (A) with nearly normal electron-dense nucleus (N) and cytoplasm having few cristae of rER. The neuropil (NP) with myelinated nerve fibers (MF) is seen; (c) an oligodendrocyte (O) with nearly normal cytoplasm and nucleus (N); (d) a part of the neuropil (NP) with nearly normal myelinated (MF) and non-myelinated (NF) nerve fibers. Other myelinated nerve fibers appeared with discontinuous and split abnormal myelin sheaths (arrow heads).
Figure 10
Figure 10
Electron micrographs of the blood–brain barrier (BBB) in the hippocampal CA1 subfields showing (a,b) intact blood capillaries (BC) with narrowed lumens (L) containing red blood cells (RBCs) and appearing with continuous and integrated basement membranes (BM) that have normal tight junctions (TJ) and surrounded by many astrocyte processes (←) in control and SM-treated rats, respectively; (c) a blood capillary (BC) surrounded with greatly expanded astrocyte processes (*) and its basement membrane was disrupted and the tight junctions were unclear, besides, the surrounding neuropil (NP) revealed vacuolation (V) are seen in AlCl3-treated rats; (d) nearly normal blood capillary (BC) enclosing red blood cells (RBCs) in its narrowed lumen and surrounded with intact basement membrane (BM) showing tight junctions (TJ), in addition, the surrounding foot processes (←) of the adjacent astrocyte appeared normal in AlCl3 + SM-treated rats.

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