As of 2021, diabetes mellitus (DM) was
responsible for an estimated USD 966 billion in global health expenditure 2021.
This represents a 316% increase over the last 15 years. The prevalence of DM is
estimated at 537 million adults surpassing the 400 million people estimated by
the World Health Organisation in 2016 (1), and is projected to reach 693 million by 2025 (2), with type 2 making up about 90% of the cases. Its incidence is
increasing rapidly, especially in Africa, with an estimated over 130% increase
in the next 25 years (3). DM occurs throughout the world but is more common (especially type
2) in developing countries. The greatest increase in prevalence is, however,
expected to occur in Asia and Africa, where most patients will probably be
found by 2045 (3).
The pathogenesis
of brain impairment caused by chronic hyperglycemia is complex and includes
mitochondrial dysfunction, neuroinflammation, neurotransmitters' alteration,
and vascular disease, which lead to cognitive impairment (CI),
neurodegeneration, and loss of synaptic plasticity, brain aging, and dementia (4, 5). Poor glycemic control has been associated with the progression of
cognitive dysfunction (6, 7). The brain pathology underlying cognitive dysfunction is
heterogeneous and highly complicated. Traditionally, Alzheimer's disease (AD)
is considered the major diagnosis of dementia (8). Although the exact pathophysiology of DM-mediated dementia has not
been fully elucidated, existing evidence has shown that both cerebrovascular changes
and neurodegeneration are implicated in the development and progression of
DM-mediated cognitive dysfunction (9).
High levels of
oxidants formed in DM by glucose oxidation, protein glycation, and the
subsequent degradation of glycated proteins, and the simultaneously declined
antioxidant enzyme levels/activities lead to cell damage, inactivation of
enzymes, and lipid peroxidation (10). Reactive oxygen species (ROS) and reactive nitrogen species (RNS)
are released from activated immune cells in response to an inflammatory
stimulus (11, ). During this, phagocytic cells release reactive oxygen and nitrogen
species (RONS), and non-phagocytic cells are stimulated to produce RONS by
pro-inflammatory cytokines (). Alpha lipoic acid has many biological functions including reducing
inflammation, chelating the transitional metal ions, and modulating the signal
transduction of nuclear factor (). It has antioxidant properties hence, can effectively inhibit
pathologies in which ROS have been implicated, such as diabetic neuropathy,
ischemia-reperfusion injury, radiation injury, and DM-induced oral implant
failure (, ). This research was aimed at determining the effect of alpha lipoic
acid on memory and oxidative stress in diabetic Wistar rats.
Declarations
Conflict of Interest
The authors declare no conflicting interest.
Data Availability
The unpublished data is available upon request to the corresponding author.
Ethics Statement
The study was approved by Bauchi State University Gadau Committee on Animal Use and Care with approval letter number of BASUG/FBMS/REC/VOL.2/23.
All drugs
and reagents were obtained commercially and were of analytical grades. The
drugs, reagents, equipment, and other materials used for the study include
alpha lipoic acid purchased from Puritan's Pride Inc. (Ronkonkoma, New York,
USA). A digital glucometer was used for blood glucose determination (Accu-Check
Advantage, Roche Diagnostic, Germany).
Animals, Induction of Diabetes,
and Experimental Design
A total of
30 male Wistar rats weighing 200 – 250 grams were used for the study. Animals
were allowed for two weeks for acclimatisation to the laboratory environment
before the commencement of the experiments. The animals were handled by
principles guiding the use and handling of experimental animals per the
universal declaration of animals rights proclaimed in Paris on 15 October, 1978
(17). Ethical approval was obtained from
Bauchi State University Gadau Committee on Animal Use and Care
(BASUG/FBMS/REC/VOL.2/23).
The rats
were fasted for 12 – 16h before the commencement of the experiment but were
allowed water ad libitum throughout the experiment. The normal groups were fed
with standard rat feed only as described by (18) and with little modification. HFD-STZ group was fed a diet with 66.5%
labina feed (52% carbohydrate, 5% lipid, 22% protein, 10% water and 11% ash),
13.5% lard, and 20% sugar. The HFD has more calories from lipids (22%) and less
carbohydrate (10%) and protein (12%) compared to the control diet. In this
research, normal groups were fed with poultry vital feed (grower marsh) (9.7%
moisture, 2 % ash, 9% crude fiber, 10% fat, 20 % crude protein and 49.3%
carbohydrate), while the high fat-diet groups were fed with a high-fat diet
(high-fat diet (HFD): 35% commercial feed, 25% groundnut, 25% fat, and 15%
groundnut oil) for the induction of obesity and DM for six weeks followed by a
single dose of streptozotocin (STZ) 40 mg/kg intraperitoneally (IP) and
high-fat diet for another 2 weeks. Rats fasted for 12h and fasting blood
glucose levels were measured to confirm the establishment of DM (18). Rats with fasting blood glucose
levels of 16 mmol/L or more were considered diabetic and selected for the study
(18). The drug administration,
estimation of fasting blood glucose level, and neurobehavioral tests were
conducted between 07:00 am – 09:00 am on day 0 (pre-treatment) and 21
(post-treatment). The rats were divided into six groups (each group had 5 rats).
All drug administrations were done orally for 21 days as follows. Group I
served as normal control and received 1 mL/kg 0.9% normal saline; Group II,
III, IV, V, and VI were all diabetic and received 1 mL/kg 0.9% normal saline, 1
mg/kg glibenclamide, 100 mg/kg ALA, 200 mg/kg ALA, 400 mg/kg ALA respectively.
Novel Object Recognition Task
The Novel
Object Recognition Task is an open-field evaluation of rats' innate propensity
to study a novel object rather than one they are familiar with. The decision to
examine the novel object and the decision to resume exploration after an object
has been moved demonstrate the use of memory and learning processes
(recognition) (19). The test was conducted between
07:00 am – 09:00 am after induction prior to the commencement of ALA
administration. The illustration below is a modification of schematic diagram
of novel object recognition task (20).
Figure 1. Schematic diagram of novel object recognition task.
This task
consists of two phases separated by a 24h period. (Retention interval): the
sample phase and the test phase. The rats were shown two identical objects
during the sample phase. These items were positioned 15 cm from each neighboring
wall in the corners of an arena. Between the sample and test phases, each rat
was put in the center of the arena and given 5min to examine the items. To get
rid of smell clues, alcohol was used to disinfect all the items. Then, during
the test phase, one of the objects was switched, and the rat was given 5min to
investigate the new object. The amount of time spent investigating the altered
objects is compared to the amount of time spent investigating the other object
(spatial memory, Ability to identify and discriminate). The rat will spend more
time investigating the altered object that was changed compared to the
unchanged object if its spatial memory and ability to discriminate and
recognize are still functional. Difference and recognition index were
calculated using Equation 1 and 2 (19, 21-23).
Difference(longtermmemory)=Tn−Tf
Equation 1
Recognitionindex=Tn+TfTn×100
Equation 2
Where Tn means time spent exploring the novel
object and Tf means time spent exploring the familiar object.
Determination of Fasting Blood
Glucose Level
The blood
samples were obtained from the rat tail vein on day 0 (pre-treatment) and day 21
(post-treatment). A digital glucometer was used to measure the blood glucose
levels using the glucose oxidase principle (24) using the digital glucometer (Accu-Check
Advantage, Roche Diagnostic, Germany), and results were expressed in mmol/L.
Termination of Experiment and
Sample Collection
On day 21,
all rats were subjected to light anesthesia by exposing them to chloroform
soaked in cotton wool and placed in an aesthetic box. Brain tissue was
collected and homogenized (25). The homogenate was used for
antioxidant and lipid peroxidation analysis.
Assessment of Antioxidant
Enzymes and Lipid Peroxidation
Catalase (CAT) Activity
Catalase
(CAT) activity was measured using the method of (26). Exactly 10 µl of homogenate was
added to a test tube containing 2.80 mL of 50 mM potassium phosphate buffer (pH
7.0). The reaction was initiated by adding 0.1 mL of freshly prepared 30 mM H2O2
and the decomposition rate of H2O2 was measured at 240 nm
for 5 min using spectrophotometer. A molar extinction coefficient (e) of
0.041 mM¯1cm¯1 was used to calculate the catalase
activity using Equation 3 and 4.
Superoxide
dismutase (SOD) was determined using the previous method (27). The basis of this assay lies in
superoxide dismutase (SOD) inhibiting the autooxidation of adrenaline at pH
10.2. The assay utilized the following reagents: a 0.05 M carbonate buffer,
prepared by dissolving 114.3 g of Na2CO3 and 4.2 g of
NaHCO3 in distilled water and adjusting the volume to 1000 mL using
a volumetric flask. The buffer's pH was then adjusted to 10.2. A fresh solution
of 0.3 mM adrenaline was made by dissolving 0.01 g of adrenaline in 17 mL of
distilled water. To create a 1:10 dilution of the microsome, 0.1 mL of tissue
homogenate was diluted with 0.9 mL of distilled water. A mixture containing 0.2
mL of the diluted microsome and 2.5 mL of 0.05 M carbonate buffer was
aliquoted. The reaction was initiated by adding 0.3 mL of 0.3 mM adrenaline.
For the reference mixture, 2.5 mL of 0.05 M carbonate buffer, 0.3 mL of 0.3 mM
adrenaline, and 0.2 mL of distilled water were combined. Absorbance readings
were taken at 480 nm over a time span of 30s to 150s. Increase in absorbance
and percentage inhibition were calculated using Equation 5 and 6.
One unit of SOD activity is the quantity of SOD necessary to elicit 50%
inhibition of the oxidation of Adrenaline to adrenochrome in one minute.
Reduced Glutathione (GSH)
Concentration
The
concentration of reduced glutathione (GSH) was determined using a previously
established method (28). To achieve this, a supernatant of
1 mL (resulting from 0.5 mL of plasma precipitated by 2 mL of 5%
trichloroacetic acid (TCA)) was utilized. Subsequently, 0.5 mL of Ellman's
reagent (0.0198% DTNB in 1% sodium citrate) and 3 mL of phosphate buffer (pH
8.0) were added to the supernatant. The resulting mixture was subjected to
colorimetric analysis by measuring the developed color at 412 nm.
Increaseinabsrobanceperminute=2.5A2−A1
Equation 5
Inhibition(
Equation 6
Lipid Peroxidation
Lipid
peroxidation in plasma was estimated colorimetrically by measuring
malondialdehyde (MDA) using the established method (29, 30). In brief, 0.1 mL of tissue
homogenate was treated with 2 mL of (1:1:1 ratio) TBA–TCA–HCL reagent (TBA
0.37%, 0.25N HCL, and 15% TCA) and placed in a water bath for 15 min, cooled
and centrifuged and then clear supernatant was measured at 535 nm against
reference blank.
Statistical Analysis
Statistical
Package for the Social Sciences version 22 (SPSS 22) was used to analyse the
data. Data obtained were presented as mean ± standard error of the mean (SEM).
Analysis of variance (ANOVA) was employed to compare the level of significance
between experimental groups and Tukey’s post
hoc test was conducted to compare between different groups while paired
T-test was used to compare within group. A significant level was considered at p<0.05.
Note: (a, p<0.001) shows significant
difference to its day 0 value, (b, p<0.001) shows significant difference compared to diabetic
control value (group II), and (c, p<0.001) shows significant difference compared to all groups on
the same day.
Result
Alpha Lipoic Acid on Fasting Blood Glucose Level in Diabetic Rats
In order to confirm the DM condition and the effect of ALA administration, we checked the blood glucose level was checked at the beginning (day 0) and end (day 21) of the experiment. There was a significant [F(5, 30) = 55.51, p<0.0001)] difference between the groups (see Table 1).
Alpha Lipoic Acid on the
Long-term and Recognition Memory in Diabetic Rats
Figure 2 illustrates the effects of ALA (at
doses of 100 mg/kg, 200 mg/kg, and 400 mg/kg) on the memory of type-2 diabetic
Wistar rats. The groups treated with 400 mg/kg (group VI) and 200 mg/kg (group
V) of ALA exhibited a significant increase (p<0.05) in the time spent
exploring the novel object after 21 days of administration compared to
pre-treatment. Furthermore, a significant increase was observed [F(5, 30) =
6.81, p<0.0001)] in the time spent exploring novel objects in the 400
mg/kg group after 21 days compared to the diabetic control group (group II:
26.24±3.81s).
Figure 3 shows the effect of ALA (100 mg/kg, 200 mg/kg and 400 mg/kg) on recognitive index of type-2 diabetic Wistar rats. The 400 mg/kg (group VI) ALA-treated groups showed a significant increase (p<0.05) in the percentage of recognition after 21 days of administration (83.77±1.49%) when compared to the pre-treatment (53.34±4.25%). Furthermore, we observed a significant increase [F(5, 30) = 3.93, p≤0.01)] in the percentage of recognition in the group VI (83.77 ± 1.49%) after 21 days compared to the diabetic control group (group II: 65.09±2.52%).
Figure 2. ALA effect on NORT in type-2 diabetic rats. Note: (a, p<0.001) shows significant difference to its day 0 value and (c, p<0.05) shows significant difference compared to diabetic control value (group II).
Figure 3. Effect of ALA on the Recognitive Index using NORT in type-2 diabetic Wistar rats. Note: (a, p<0.05) shows significant difference to its day 0 value and (b, p<0.05) shows significant difference compared to diabetic control group (group II).
Table 2. Changes in biomarkers of oxidative stress and lipid peroxidation in alpha lipoic acid treated type-2 diabetic wistar rats.
Groups
Catalase (IU/mg)
SOD (IU/mg)
Percentage SOD Inhibition (%)
GSH (μg/mL)
MDA (nmol/L)
I
1.57 ± 0.09a
0.84 ± 0.05a
42.00 ± 0.01a
93.20 ± 5.30a
2.20 ± 0.25a
II
0.84
± 0.03
0.49
± 0.03
25.13
± 1.41
51.64
± 0.87
7.22
± 0.42
III
1.38 ± 0.03a
0.71 ± 0.04a
35.08 ± 1.98a
60.18 ± 1.95a
4.50 ± 0.19a
IV
1.32
± 0.33a
0.70
± 0.04a
35.52
± 2.00a
69.06
± 0.89a
4.78
± 0.34a
V
1.69 ± 0.01a
0.98 ± 0.03a
48.80 ± 1.57a
78.48 ± 1.37a
3.64 ± 0.18a
VI
1.76
± 0.02a
1.02
± 0.03a
50.98
± 1.68a
91.08
± 3.49a
3.60
± 0.25a
Note: (a, p<0.05)
shows significant difference compared to diabetic control value (group II).
Alpha Lipoic Acid on Level of Antioxidant Enzymes in Diabetic Rats
We also evaluated the concentration of catalase in the brain homogenate (Table 2) in the diabetic rats after 21 days of ALA administration at different doses (100 mg/kg, 200 mg/kg, and 400 mg/kg). We observed a significant [F(5, 30) = 5.69, p<0.001)] increase in the concentration of CAT level in the 200 mg/kg and 400 mg/kg groups (group V: 1.69±0.01 IU/mg and group VI: 1.76±0.02 IU/mg) compared to the diabetic control group (0.84±0.03 IU/mg).
Furthermore, the activity of SOD in the brain homogenate (Table 2) in the diabetic rats after 21 days of ALA administration at different doses (100 mg/kg, 200 mg/kg, and 400 mg/kg) were improved based on the findings of this study. We observed a significant [F(5, 30) = 27.40, p<0.0001)] increase in the concentration of SOD in the groups treated with ALA at 200 mg/kg and 400 mg/kg (groups V and VI) as well as glibenclamide (group III) with values of 0.98±0.03 IU/mg, 1.02±0.71 IU/mg and 0.71±0.04 IU/mg respectively compared to the diabetic control group (0.49±0.03 IU/mg).
The activity of GSH in the brain homogenate (Table 2) in the diabetic rats after 21 days of ALA administration at different doses (100 mg/kg, 200 mg/kg and 400 mg/kg) were also improved. We observed significant [F(5, 30) = 52.11, p<0.0001)] increase in the concentration of GSH in all the groups treated with glibenclamide (group III) and ALA (Groups IV, V and VI) with values of 60.18±1.95 μg/mL and 69.06±0.89 μg/mL, 78.48±1.37 μg/mL and 91.08±3.49 μg/mL respectively compared to the diabetic control group (51.64±0.87 μg/mL).
The marker of lipid peroxidation (MDA) was determined using brain homogenate (see Table 2) in the diabetic rats after 21 days of ALA administration at different doses (100 mg/kg, 200 mg/kg and 400 mg/kg). We found a significant [F(5, 30) = 34.36, p<0.0001)] decrease in the concentration of MDA in all the groups treated with glibenclamide (group III) and ALA (Groups IV, V and VI) with values of 4.50±0.19 nmol/mg and 4.78±0.34 nmol/mg, 3.64±0.18 nmol/mg and 3.60±0.25 nmol/mg respectively compared to the diabetic control group (7.22±0.42 nmol/mg).
Discussion
Several scientific researchers had over the
years associated DM with peripheral nerve damage, Alzheimer’s disease and CI.
DM also negatively impacts the lipid- and protein-intermediate metabolism (31-33). It was postulated that hyperglycemia, oxidative stress,
dyslipidemia and inflammation are the major mediators for the pathogenesis and
progression of memory impairment in DM (34, 35). Alpha lipoic acid (ALA) has been used for some years now as an
antioxidant with antihyperglycemic and anti-inflammatory supplement and due to
its extensive range of pharmacological activity, treat various illnesses (36, 37).
The results obtained in this study
indicated that DM has affected long-term memory in NORT in type-2 diabetic rats.
There was a significant (p<0.05)
difference between day 0 and day 21 of the diabetic untreated group (group II).
This indicated that DM has affected long-term memory in NORT. However, we
observed a significant increase in long-term memory in the ALA groups after 21
days compared to the pre-treatment. This could be associated with the
antihyperglycemic as seen in this study and antilipidemic effect of ALA (38). This aligns with a prior study indicating that ALA enhances mouse
memory, assessed through the Barnes test (36). Furthermore, Ko CY, et al. (2021) reported that ALA may ameliorate
cognition impairment via alleviating cerebral IR improvement and cerebral
synaptic plasticity in diabetic rats (37).
The gradual decrease in the recognition
index observed in the diabetic untreated group of the present study further confirms
memory impairment induced by DM. This may be associated with hyperglycemia and
oxidative stress which have been implicated in learning and memory impairment.
We also observed an improvement in all the ALA-treated groups with the highest
dose showing a significantly higher effect compared to the diabetic untreated
group after 21 days of administration. From the result observed in the ALA-treated group, it is evident that
hyperglycemia is associated with impairment of long-term and recognition ability
in the experimental animals which was significantly improved (p<0.05) by the daily administration
of ALA as seen in the groups treated with 100 mg/kg, 200 mg/kg and 400 mg/kg of
ALA. This improvement may be associated with ALA’s antihyperglycemic and antioxidant
effects as demonstrated in our results (39-41) and lipid lowering effect as demonstrated by previous study (38). However, this finding contradicts the findings of Villasana LE, et
al. (2013) who reported ALA treatment impaired cortical-dependent novel object
recognition in experimental animals (42). This could be because the memory impairment in the present study
was secondary to diabetes, not irradiation or the doses used in the present
study.
Reactive oxygen species (ROS) are released
from activated immune cells in response to an inflammatory stimulus. The
balance between the rate of free radical generation and elimination is
important. Excess cellular radical generation can be harmful (39). The SOD offers first line of defense against ROS by scavenging and
catalyzing the dismutation of superoxide, produced by cellular metabolism, into
hydrogen peroxide (H2O2) and oxygen (O2) (40). Reduced glutathione reduces the oxidized form of the enzyme
glutathione peroxidase, which in turn reduces hydrogen peroxide (H2O2),
a dangerously reactive species within the cell (43). In this research, we found a significant improvement in the brain-homogenated
antioxidant enzymes across the different doses of ALA. This further signifies
the effectiveness of ALA in free radicals scavenging (44). Oxidative stress and free radicals have been implicated in most if
not all of the complications of DM and diabetes-induced CI (45). This action of ALA has further explained the mechanism through
which long-term and recognition memories were improved as seen in Figures 2 and
3, respectively. Furthermore, we also observed a significant reduction in the
biomarker of lipid peroxidation (MDA). This further signifies that ALA at all
the doses tested improved membrane integrity by reducing lipid peroxidation.
This finding agrees with many other findings that reported antioxidant activity
of ALA in experimental animals.
Conclusion
Results obtained in the present study
demonstrated that type-2 DM causes memory impairment by affecting long-term and
recognition memory in novel object recognition task through hyperglycemia and
oxidative stress. This significantly improved after 21 days of administration
of ALA (p<0.05). The activities of
antioxidant enzymes were also improved with significant decrease in lipid
peroxidation (p<0.05). This
signifies that ALA could be a potential therapeutic target for memory
impairment associated with type-2 DM.
Diabetes mellitus (DM) and oxidative stress are among the leading causes of memory loss and dementia. Dietary supplements have been used to manage many disorders. This research aimed to determine the effect of alpha lipoic acid (ALA) on memory and oxidative stress in diabetic Wistar rats. 30 rats were grouped into six (5 in each). Diabetes was induced using a high-fat diet followed by a single low dose of streptozotocin (40 mg/kg) intraperitoneally. Group I served as normoglycemic control (1 mL/kg normal saline), while groups II, III, IV, V, and VI were diabetic and received 1 mL/kg at normal saline, glibenclamide at 1 mg/kg, ALA at 100 mg/kg, 200 mg/kg and 400 mg/kg respectively for 21 days. Blood glucose level was determined before and after treatment. Long-term and recognition memory were determined using novel object recognition tasks (NORT). Brain tissues were used for antioxidant enzymes. The result obtained showed that at 400 mg/kg after 21 days of administration of ALA, long-term memory and recognition ability were increased significantly (45.65±3.43s and 83.77±1.49%) compared to the diabetic control (26.24 ± 3.81s and 65.09 ± 2.52%) respectively. Antioxidant enzymes’ levels were increased significantly in the group VI including catalase (1.76±0.02 IU/mg) superoxide dismutase (1.02±0.71 IU/mg) and reduced glutathione (91.08±3.49 µg/mL) compared to the diabetic control group (0.84±0.03 IU/mg, 0.49±0.03 IU/mg and 51.64±0.87 µg/mL) respectively. The findings suggest that ALA has antioxidant activity and improves memory in diabetic Wistar rats.
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