INTRODUCTION:

The average weight of an adult human brain is between 1300 and 1400grams. 15 centimeters in length, anatomically situated within the skull, and encased in cerebrospinal fluid. Even though the human brain is the most powerful organ with amazing powers, it is also susceptible to a number of dysfunctions that can be brought on by a number of things, including severe and unexpected head injuries, infections, drug and alcohol abuse, seizures, epilepsy, and a reduction in oxygen supply to the brain from a stroke¹.

The slow progression of a neurodegenerative disease in the central nervous system (CNS) eventually results in the death of nerve cells, which is followed by impairments in speech, learning, and cognition. Both the Cardinal and Disease Proteins features can be used to classify neurodegenerative diseases². Dementias like Alzheimer's disease, movement disorders like Parkinson's or Huntington's disease, cerebellar ataxias, and motor neuron diseases like amyotrophic lateral sclerosis are all identified by the Cardinal Characterization³.

In contrast to clinical death, dementia, which is generally referred to as memory loss, might be described as a "philosophical death." The most prevalent type of dementia, accounting for 60–70% of cases, is Alzheimer's disease. About 5–8% of people worldwide who are 60 years of age or older have dementia at any given moment. It is estimated that by 2030, there will be 82 million people with dementia, and by 2050, there will be 152 million⁴.

Alzheimer's disease is a progressive neurological disease for which the drugs now on the market are ineffective since they only address the symptoms. Alzheimer's disease is thought to begin as early as age 20 or even before symptoms show up but are invisible to the afflicted individual⁵. After a few years, people start to show serious symptoms including memory loss and language problems attributed to intracellular and extracellular Amyloid β (Aβ) plaques. Even though symptoms can vary widely, many people first struggle with mild forgetfulness and uncertainty, which can eventually lead to complete memory loss, difficulties making decisions, and even difficulties with daily routine activities. Personality changes and other symptoms like depression, mood swings, anger, and detachment from society are then common⁶. Neurons in certain brain regions related to cognition, learning, and memory (cognitive function) get weaker or die as the disease worsens. Lastly, people become bedridden, need round-the-clock care, and die. Additionally, there is currently no standard way to examine Alzheimer's disease; nevertheless, doctors can look at symptoms and medication history to rule out other disorders before making a diagnosis⁷.

The Impact of D-Galactose on Biology:

Even though there are many different kinds of animal models for aging⁸, the D-galactose-induced aging model is frequently used for a number of neurological disorders linked to aging, including Parkinson's, Huntington's, and Alzheimer's diseases, because it not only speeds up the induction of AD but also causes "brain senescence" more readily, with fewer side effects, and in a shorter amount of time than the natural aging process⁹. According to several earlier investigations, D-galactose ages the brain by causing oxidative stress and mitochondrial dysfunction¹⁰. Therefore, the method of IP injection of D-galactose (D-gal) was employed in the current study to induce Alzheimer's disease.

Herbs in Treatment of AD:

The foundation of herbal therapies is a holistic approach to care that promotes and maintains equilibrium in the body, mind, and soul, among other areas of human existence. The most important stage of drug development from natural sources is choosing the best starting materials based on ethnobotanical, ethnomedicinal, and folkloric usage. Phytochemicals are appealing therapeutic agents for neurodegenerative disorders due to their anti-inflammatory, antioxidant, and anticholinesterase properties¹¹.

In the current work, the memory-boosting effects of red grape (Vitis vinifera L.) seed extract were evaluated in an albino rat model induced by AD. Grapes are members of the vine family and belong to the genus Vitis. Procyanidins and catechins, which have potent antioxidant properties and scavenge free radicals, are abundant in grape seeds^12,16-18.

MATERIAL AND METHOD:

The department head confirmed that the red grape seed sample used in this study was locally sourced. Every other chemical and reagent utilized in this investigation was of analytical quality.

The Acquisition of and Upkeep of Experimental Animals:

Forty-eight healthy male Wistar rats (3 months old), weighing 180±20g, were procured from an authorized dealer for the study. The animals were housed in the institutional animal research facility under standard laboratory conditions (temperature: 22±2°C; relative humidity: 50–60%; 12-hour light/12-hour dark photoperiod) with free access to standard pellet diet and water ad libitum. Prior to the commencement of the experiment, the animals were acclimatized to the laboratory environment for 10 days. All experimental procedures were reviewed and approved by the Institutional Animal Ethics Committee (IAEC) in accordance with the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Government of India, under approval number SOP/CEC/IAEC/2024-25/037.

Developing an Extract from Grape Seeds:

Clusters of red grapes were allowed to air dry in a shaded area for a week before being ground. The 'Red Grape Seed Extract' (RGSE) was then collected as a lyophilized powder after being macerated in 75% ethanol for 72hours and then the ethanolic extract was fully evaporated to remove the ethanol¹³. To create a concentrated solution, 10g of the aforementioned grape seed powder was cooked in 200ml of distilled water and then heated to 60–70°C. A rotary vacuum evaporator was used to concentrate the extracts after they had first been filtered using muslin cloth and Whatman no. 1 filter paper. The remaining material was then gathered, dried, and kept for future research.

Grouping of Animals And Induction of Ad:

The D-galactose-induced aging model is frequently used to study a number of aging-related neurological conditions. The medication was administered via intraperitoneal injection (IP). Four groups of rats were randomly selected. Two subgroups of six each were formed from each main group and kept in different cages. All doses were administered once in the morning, between 8 and 9 am, in consideration of the rats' changed activity at night as opposed to during the day. Red grape seed was administered in specific dosages to each of these rat groups, with the exception of the control group.

Various experimental groups:

Group I Control group: Rats given a subcutaneous injection of saline (1ml/kg body weight).

Group II Red Grape Seed Extract (RGSE group): Rats received saline injections during the first six weeks, then starting in the seventh week, they were given an oral dose of Red Grape Seed Extract (RGSE) ethanol extract (100mg/kg body weight) for 60 days.

Group III AD-Induced group (AD-I): Until the experiment's conclusion, rats received intraperitoneal (IP) D-Gal at a dose of 120mg/kg body weight.

Group IV Administered with D-Gal + Red Grape Seed Extract (AD-I + RGSE group): Rats were administered D-Galactose (120mg/kg body weight) via intraperitoneal injection for a period of six weeks, followed by oral administration of Red Grape Seed Ethanol Extract (100mg/kg body weight) simultaneously for an additional sixty-day period.

Biochemical Estimation:

The chosen isolated tissue homogenate of the experimental animals will be used to estimate different glutamatergic system components. On the 30th and 60th days of the experiment, the rats were sacrificed after being fasted for 12hours. Glutamate Dehydrogenase (GDH), glutamine synthetase (GS), glutamine content (GC), and glutaminase activity (GA) are among them.

Statistical Analysis:

Every experiment was conducted in triplicate and reported as Mean±SD. The significance of the differences between the various experimental groups was tested using a one-way ANOVA.

RESULT AND DISCUSSION:

Glutamine Content:

On 30th Day:

According to the study's findings, the hippocampal region had the highest amount of glutamine in the control brain (112.27), followed by the cerebellum (104.03), cerebral cortex (101.97), and pons medulla (98.88). In contrast, the rats in the group treated with Red Grape Seed Extract (RGSE) alone had lower levels of glutamine. In contrast, when compared to other brain regions, the medulla of the AD-induced rats showed the highest increase of glutamine (14.58%), followed by the hippocampal region (-7.58%). Remarkably, when Red Grape Seed Extract (RGSE) was given orally to AD-induced rats, the glutamine levels recovered in the following order: Pons Medulla (9.37%) >Cerebellum (8.91%) >Cerebral Cortex (5.05%) >Hippocampus (1.83%).

On 60th Day:

The glutamine concentration in different brain regions from all four groups of rats showed a nearly identical trend, with just slight variations on the 60th day of the experiment. Based on these findings, it was determined that the protected group of rats given RGSE showed a noteworthy recovery trend in their glutamine levels. Results are shown in Figure 1 and Tables 1 and 2.

Table 1: Glutamine content expressed as ammonia formed in μ moles per protein mg per hour

Study categories	Regions of Brain
	PM		HP		CC		CB
	30^th day	60^th day	30^th day	60^th day	30^th day	60^th day	30^th day	60^th day
Reference	98.88	107.12	112.27	109.18	101.97	115.36	104.03	105.06
Reference	±5.64	±6.11	±6.41	±6.23	±4.95	±6.58	±5.94	±5.99
RGSE	100.94	115.36	105.06	118.45	115.36	113.3	109.18	109.18
	±5.76	±6.58	±5.99	±6.76	±6.58	±6.46	±6.23	±6.23
	(2.08)	(7.69)	(-6.42)	(8.49)	(13.13)	(-1.79)	(4.95)	(3.92)
AD-I	113.3	83.43	120.78	76.22	84.46	135.96	89.61	120.51
	±6.46	±4.76	±5.87	±4.35	±4.82	±7.76	±5.11	± 6.88
	(14.58)	(22.12)	(-7.58)	(30.19)	(17.17)	(17.86)	(13.86)	(14.71)
AD-I + RGSE	108.15	91.67	110.21	105.06	96.82	127.72	94.76	115.36
	±6.17	±5.23	±6.29	±5.99	±5.52	±7.29	±5.41	±6.58
	(9.37)	(14.42)	(1.83)	(3.77)	(5.05)	(10.71)	(8.91)	(9.80)

The data represents the mean ± SEM of six observations, with tissues pooled from six rats. Percent changes relative to the control are shown in parentheses. Significant differences from the control group are indicated at p < 0.05.

Table 2: ANOVA Glutamine Content

Glutamine Content		df	Sum of Squares	F value	Mean Square	Sig.
CC 60^th day	Within Groups	20	697.583		34.879
	Between Groups	3	5975.585	57.108	1991.862	.000
	Total	23	6673.168
HC 60^th day	Within Groups	20	993.316		49.666
	Between Groups	3	2056.015	13.799	685.338	.000
	Total	23	3049.331
CB 60^th day	Within Groups	20	654.359		32.718
	Between Groups	3	3774.65	38.456	1258.217	.000
	Total	23	4429.01
PM 60^th day	Within Groups	20	827.826		41.391
	Between Groups	3	832.269	6.702	277.423	.000
	Total	23	1660.096
CC 30^th day	Within Groups	20	608.802		30.44
	Between Groups	3	2945.59	32.256	981.863	.000
	Total	23	3554.392
HC 30^th day	Within Groups	20	755.65		37.782
	Between Groups	3	771.037	6.802	257.012	.000
	Total	23	1526.687
CB 30^th day	Within Groups	20	647.947		32.397
	Between Groups	3	1406.782	14.474	468.927	.000
	Total	23	2054.729
PM 30^th day	Within Groups	20	725.329		36.266
	Between Groups	3	794.071	7.298	264.69	.000
	Total	23	1519.399

Table 3: Glutamine Synthetase activity as micromoles of γ-glutamyl hydroxamate formed per milligram of protein per hour, was measured in specific regions of the brain

Study categories	Brain Regions
	HP		PM		CC		CB
	60^th day	30^th day	60^th day	30^th day	60^th day	30^th day	60^th day	30^th day
	1.060	0.948	0.536	0.497	0.814	0.713	0.816	0.692
AD-I	±0.051	±0.054	±0.030	±0.029	±0.047	±0.041	±0.047	±0.039
	(65.89)	(58.60)	(15.28)	(12.07)	(29.46)	(33.11)	(37.53)	(35.49)
	0.639	0.598	0.465	0.443	0.629	0.536	0.593	0.511
Control
	±0.037	±0.034	±0.027	±0.025	±0.036	±0.030	±0.034	±0.029
	0.862	0.775	0.569	0.528	0.710	0.598	0.713	0.610
AD-I +
RGSE	±0.042	±0.044	±0.032	±0.030	±0.041	±0.034	±0.041	±0.035
	(35.02)	(29.62)	(22.39)	(19.07)	(12.88)	(11.57)	(20.17)	(19.34)
	0.444	0.476	0.396	0.406	0.545	0.485	0.455	0.465
RGSE	±0.025	±0.027	±0.020	±0.17	±0.031	±0.028	±0.026	±0.027
	(- 30.48)	(-20.33)	(-14.85)	(-8.27)	(-13.31)	(-9.43)	(-23.23)	(-9.07)

The data represents the mean±SEM of six observations, with tissues pooled from six rats. Percent changes relative to the control are shown in parentheses. Significant differences from the control group are indicated at p<0.05

Table 4: Glutamine Synthetase - ANOVA

Glutamine Synthetase		df	Sum of Squares	F	Mean Square	Sig.
CC 60^th day	Within Groups	20	0.03		0.002
	Between Groups	3	0.237	52.151	0.079	.000
	Total	23	0.267
HC 60^th day	Within Groups	20	0.032		0.002
	Between Groups	3	1.287	269.119	0.429	.000
	Total	23	1.318
CB 60^th day	Within Groups	20	0.029		0.001
	Between Groups	3	0.435	101.512	0.145	.000
	Total	23	0.463
PM 60^th day	Within Groups	20	0.016		0.001
	Between Groups	3	0.107	44.803	0.036	.000
	Total	23	0.123
HC 30^th day	Within Groups	20	0.034		0.002
	Between Groups	3	0.765	150.218	0.255	.000
	Total	23	0.799
CC 30^th day	Within Groups	20	0.023		0.001
	Between Groups	3	0.174	50.923	0.058	.000
	Total	23	0.196
CB 30^th day	Within Groups	20	0.022		0.001
	Between Groups	3	0.187	57.535	0.062	.000
	Total	23	0.208
PM 30^th day	Within Groups	20	0.013		0.001
	Between Groups	3	0.053	26.601	0.018	.000
	Total	23	0.066

Table 5: Glutamate Dehydrogenase (GDH) activity levels (micromoles of formazan formed per milligram of protein per hour) were measured in specific brain regions

Study categories	Brain Regions
	HP		CC		PM		CB
	60^th day	30^th day	60^th day	30^th day	60^th day	30^th day	60^th day	30^th day
	4.007	3.780	3.839	3.548	3.849	3.632	2.866	2.704
	3.537	3.337	2.816	2.656	2.743	2.743	2.290	2.160
AD-I	±0.202	±0.190	±0.161	±0.152	±0.157	±0.157	±0.131	±0.123
	(-11.72)	(-11.72)	(-26.66)	(-25.13)	(-28.74)	(-24.48)	(-20.13)	(-20.11)
Control
	±0.229	±0.216	±0.219	±0.171	±0.220	±0.207	±0.163	±0.154
	4.206	3.968	3.533	3.333	3.930	3.708	2.376	2.241
AD-I + RGSE	±0.240	±0.227	±0.202	±0.190	±0.224	±0.212	±0.136	±0.128
	(4.96)	(4.96)	(7.97)	(6.06)	(2.11)	(2.10)	(17.12)	(17.10)
	4.300	4.300	4.921	4.642	5.100	5.100	4.902	4.625
RGSE	±0.246	±0.246	±0.281	±0.265	±0.291	±0.291	±0.280	±0.264
	(7.32)	(13.76)	(28.17)	(30.84)	(32.48)	(40.41)	(71.02)	(71.05)

Table 6: ANOVA Glutamine Dehydrogenase

Glutamate Dehydrogenase		df	Sum of Squares	F	Mean Square	Sig.
CC 60^th day	Within Groups	20	0.968		0.048
	Between Groups	3	13.773	94.852	4.591	.000
	Total	23	14.741
HC 60^th day	Within Groups	20	1.055		0.053
	Between Groups	3	2.075	13.107	0.692	.000
	Total	23	3.13
CB 60^th day	Within Groups	20	0.703		0.035
	Between Groups	3	26.901	255.216	8.967	.000
	Total	23	27.604
PM 60^th day	Within Groups	20	1.04		0.052
	Between Groups	3	16.687	107.018	5.562	.000
	Total	23	17.726
CC 30^th day	Within Groups	20	0.794		0.04
	Between Groups	3	12.231	102.681	4.077	.000
	Total	23	13.025
HC 30^th day	Within Groups	20	0.972		0.049
	Between Groups	3	2.908	19.938	0.969	.000
	Total	23	3.88
CB 30^th day	Within Groups	20	0.626		0.031
	Between Groups	3	23.943	255.116	7.981	.000
	Total	23	24.569
PM 30^th day	Within Groups	20	0.986		0.049
	Between Groups	3	17.058	115.38	5.686	.000
	Total	23	18.043

Table 7: Glutaminase (Gln.ase) activity as micromoles of ammonia formed per milligram of protein per hour, was assessed in specific brain regions.

Study categories

Brain Regions

60^th day

30^th day

60^th day

30^th day

60^th day

30^th day

60^th day

30^th day

AD-I

5.92

±0.28

(62.27)

5.09

±0.26

(53.77)

7.68

±0.43

(61.25)

6.71

±0.35

(55.34)

6.855

±0.391

(34.33)

6.522

±0.341

(34.33)

6.107

±0.349

(70.42)

5.810

±0.304

(70.42)

Control

3.65±0.20

3.31±0.16

4.76±0.27

4.32±0.21

5.103±0.291

4.855±0.254

3.583±0.205

3.409 ±0.179

AD-I + RGSE

4.300

±0.225

(17.71)

4.48

±0.23

(35.23)

5.49

±0.28

(15.19)

5.71

±0.29

(32.33)

5.602

±0.293

(9.79)

5.836

±0.306

(20.20)

4.611

±0.241

(28.67)

4.803

±0.251

(40.87)

RGSE

3.08

±0.16

(-15.60)

3.08

±0.16

(-6.92)

3.52

±0.18

(-25.96)

3.60

±0.18

(-16.68)

3.267

±0.170

(-35.98)

3.266

±0.171

(-32.73)

2.451

±0.128

(-31.60)

2.553

±0.133

(-25.11)

The data represents the mean±SEM of six observations, with tissues pooled from six rats. Percent changes relative to the control are shown in parentheses. Significant differences from the control group are indicated at p < 0.05

Table 8: ANOVA Glutaminase Activity

Glutaminase Activity		df	Sum of Squares	F	Mean Square	Sig.
CC 60^th day	Within Groups	20	1.917		0.096
	Between Groups	3	54.774	190.492	18.258	.000
	Total	23	56.691
HC 60^th day	Within Groups	20	1.015		0.051
	Between Groups	3	27.216	178.672	9.072	.000
	Total	23	28.231
CB 60^th day	Within Groups	20	1.191		0.06
	Between Groups	3	43.461	243.192	14.487	.000
	Total	23	44.652
PM 60^th day	Within Groups	20	1.765		0.088
	Between Groups	3	39.885	150.634	13.295	.000
	Total	23	41.651
CC 30^th day	Within Groups	20	1.464		0.073
	Between Groups	3	35.032	159.569	11.677	.000
	Total	23	36.495
HC 30^th day	Within Groups	20	0.891		0.045
	Between Groups	3	16.438	123.017	5.479	.000
	Total	23	17.329
CB 30^th day	Within Groups	20	1.027		0.051
	Between Groups	3	37.692	244.637	12.564	.000
	Total	23	38.719
PM 30^th day	Within Groups	20	1.518		0.076
	Between Groups	3	35.922	157.774	11.974	.000
	Total	23	37.44

Figure 4: Glutaminase (Gln.ase) activity as micromoles of ammonia formed per milligram of protein per hour, was assessed in specific brain regions

This study evaluated the impact of Red Grape Seed Extract (RGSE) on AD-induced changes in glutamate metabolism, focusing on glutaminase, glutamine, glutamic acid dehydrogenase activities, and glutamine synthetase, across four brain regions of male albino rats: the cerebral cortex, hippocampal region, cerebellum, and pons medulla.

The research findings demonstrated higher "Glutamine" levels in both the Hippocampus and Pons medulla brain regions of the experimental group when compared with reference group at both 60th plus 30th days of the study. Results demonstrated that Red Grape Seed Extract (RGSE) therapy given to AD model rats repaired these observed alterations.

The current study assessed and compared the effects of Red Grape Seed Extract (RGSE) on the AD-induced alterations in glutamate metabolism, specifically glutaminase, glutamine, glutamic acid dehydrogenase activities, and glutamine synthetase, in four specific brain regions of male albino rats: the cerebral cortex, hippocampal, cerebellum, and pons medulla. The data in this study show that AD pathology is caused by aberrant glutamate neuro-transmission in addition to glutamate–glutamine cycle imbalances, which also play a major role in the advancement of neuronal death.

SUMMARY AND CONCLUSION:

The progressive neurodegenerative disease known as "Alzheimer's Disease," which is frequently seen in those over 65, typically starts with a slow deterioration in memory, cognition, and activity-related problems before leading to irreversible cognitive loss. The goal of the current study was to create possible anti-alzheimer's chemical compounds from "Red Grape Seed Extract (RGSE)," which contains bioactive substances including "Pro-Anthocyanidins" and "Phenolic antioxidants." "Resveratrol" (trans-3,4,5 trihydroxy stilbene), a non-flavonoid polyphenol that is found in large quantities in grapes and red wine, is known to have antioxidant and life-extending properties^14,15. As previously established, "Resveratrol" has a neuro-protective effect by facilitating the removal of senile plaques and preventing the neurotoxic effects of βAPs. RGSE enhanced with the aforementioned substances can reduce oxidative stress, in vitro amyloid-β buildup, and neurotoxicity. Glutamine Synthetase transforms glutamate into glutamine, and glutamine levels in brain tissues help to maintain glutamate concentration for both its neurotransmitter pool and its overall role as an amino acid. As a chemical that stores and transports ammonia in different tissues, glutamine is also produced as a defense mechanism to keep ammonia concentrations in tissues low. Therefore, RGSEs' potential advantages may be partially explained by their antioxidant properties and ability to inhibit glutamate activity in the brain. To ascertain the effectiveness of RGSE in rats with AD, however, further thorough investigation is required.

CONFLICT OF INTEREST STATEMENT:

The authors declare that there is no conflict of interest regarding the publication of this study.

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Received on 14.06.2025 Revised on 11.07.2025

Accepted on 05.08.2025 Published on 11.10.2025

Available online from October 25, 2025

Res.J. Pharmacology and Pharmacodynamics.2025;17(4):243-251.

DOI: 10.52711/2321-5836.2025.00039

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Creative Commons License.

The Impact of D-Galactose on Biology:

Herbs in Treatment of AD:

MATERIAL AND METHOD:

The department head confirmed that the red grape seed sample used in this study was locally sourced. Every other chemical and reagent utilized in this investigation was of analytical quality.

The Acquisition of and Upkeep of Experimental Animals:

Developing an Extract from Grape Seeds:

Grouping of Animals And Induction of Ad:

Various experimental groups:

Biochemical Estimation:

Statistical Analysis:

RESULT AND DISCUSSION:

Glutamine Content:

On 30th Day:

On 60th Day:

Glutamine Synthetase (GS):

On 30^th Day:

On 60^th Day:

Glutamate Dehydrogenase (GDH):

On 30^th Day:

On 60^th Day:

Glutaminase Action:

On 30^th Day:

On 60^th Day:

SUMMARY AND CONCLUSION:

REFERENCES: