INTRODUCTION:

Vascular dementia (VaD), the second most occurring form of dementia, is characterized by cognitive impairment, which is quantified as a deficit in memory, cognition, executive function, language, attention, and behavior¹. VaD occurs as a result of an impaired vascular system that disrupts the sufficient supply of blood and hence oxygen as well as nutrients to the brain that ultimately cause neuronal cell death².

Cardiovascular risk factors such as hypertension have been associated with the increased incidence, onset, and progression rate of dementia that is of vascular origin³. Optimal treatment of these risk factors provides a key measure in preventing the development of VaD.

Hypertension causes microvascular dysfunction that lead to white matter disease, microinfarcts as well as microhemorrhages⁴.These cerebrovascular lesions impair continuous supply of blood to the highly vascularized organ, “brain”. Inadequate supply to the brain damages the cerebral vasculature and compromise delivery of oxygen and glucose for proper neuronal functions⁵. This causes cognitive decline and impairment⁴. Two-kidney one-clip (2K1C) model has already been established for the induction of renovascular hypertension stimulated VaD in rats^6-7. Therefore, present study utilizes 2K1C model for the induction of endothelial dysfunction associated VaD in rats.

An ergot derivative, nicergoline protective effects has been observed against several brain disorders such as Alzheimer’s disease, Parkinson’s disease, ischemic stroke, and other vascular disease⁸. Nicergoline effect has been studied to improve the integrity of the BBB⁹.Nicergoline improve learning, memory, judgement, reasoning, perception, spatial learning, cognitive dysfunction as well as spontaneous plasticity^9-11. Administration of nicergoline provides beneficial effect against oxidative stress, inflammation and endothelial dysfunction^9,12. Nicergoline administration ameliorates neuronal apoptosis, neuronal loss, and cognitive competence in the hippocampal cells via reduction of inflammatory pathway as well as oxidative stress¹¹. Nicergoline promotes neuronal survival as well as neuronal genesis¹³. Treatment with nicergoline increases neuronal nitric oxide synthase expression that results in improved blood-brain perfusion¹³. Clinical and in-vitro studies have also shown the protective effects of nicergoline against endothelial dysfunction, oxidative stress, inflammation and neuronal apoptosis¹¹. Role of nicergoline has been studied for various brain conditions but the utility of nicergoline has not been studied in 2K1C model induced endothelial dysfunction and associated VaD.

In the light of above, we hypothesized that nicergoline, may provide beneficial effects in 2K1C model induced endothelial dysfunction and associated VaD and thus, the present study has been designed. Animals’were assessed for behaviour (Morris water maze-MWM, attentional set shifting tests (ASST)), vascular endothelial function, cerebral oxidative stress (thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, superoxide dismutase-SOD, and catalase-CAT), inflammation (myeloperoxidase-MPO), calcium levels and acetylcholinesterase activity- AChE activity.

MATERIALS AND METHODS:

Animals:

The present study employed age matched adult male Albino Wistar rats weighing around 200-250 gm (2- 3 months old). The experiments were conducted as per the study protocol approved by IAEC, following the guidelines provided by CPCSEA

Drugs and chemicals:

All the drug solutions were prepared freshly before use.

Two-kidney-one-clip (2K1C) renovascular hypertension induced VaD

2K1C model is a well-established renovascular hypertension model that increases the mean arterial blood pressure (MABP). 2K1C model was established as mentioned in Singh et al., 2015 ⁷. During experiments, animals were taken well care off and were provided with proper food and water.

Experimental protocol:

In the present study, a total of eleven groups were employed with each group consisting of six animals of either sex albino Wistar rats. Initially, animals were exposed to renal artery ligation. Animals were randomly divided into eleven groups with each group consisting of 6 rats.

Group- I: Sham Control Group: Animals underwent sham surgery without ligation of the renal artery post which, they were sutured back.

Group- II and III: Sham and vehicle treated group (Carboxymethyl cellulose (CMC) and saline)- Rats underwent sham surgery, were administered with CMC 0.5% W/V (10 ml/Kg p.o.) or saline (0.9% w/v; 10ml/kg, i.p) once daily during 4 weeks.

Group IV, V, VI: Sham and nicergoline (dose 1 or 2) or donepezil groups: Rats underwent sham surgery, were administered with nicergoline (5 mg/kg or 10 mg/kg p.o.) or donepezil (1.0 mg/kg i.p.) daily for 4 weeks ¹⁵.

Group VII: 2K1C group: Left renal artery of the animals in this group were ligated using silk suture.

Group VIII, IX and X: 2K1C and nicergoline (dose 1 or 2) or donepezil groups: Left renal artery of the animals in this group were ligated using silk suture. Furthermore., these animals were administered with nicergoline (5 mg/kg or 10 mg/kg) or Donepezil (1 mg/kg i.p.) daily for 4 weeks.

Drug Administration:

Drug solutions were prepared freshly before use. Doses and the dosing scheduled were selected according to the preliminary data as well as the previous published reports. 2K1C has been known to induce hypertension within 7 days after surgery¹⁴. Treatment with nicergoline was initiated on the 15^th day because for first 14 days rats were allowed to recover from the surgery related stress and acquire hypertension. Furthermore, it was observed that 2K1C hypertension induced endothelial dysfunction was observed during 14-15^th day (2 weeks). Behavioral assessments were conducted at the end of the study starting from 33^rdonwards till 42^nd day.

Assessment of learning and memory:

MWM was used to assess spatial learning and memory whereas, ASST was used for measuring reversal learning and executive functioning in animals^{7, 16-17}.

Assessment of vascular endothelial function:

ACh induced endothelium dependent and SNP induced endothelium independent relaxation were assessed, as per the previously published reports using aortic ring preparations^16-21.

Estimation of mean arterial blood pressure, serum nitrite/nitrate, aortic superoxide anion and brain total protein, oxidative stress (TBARS, GSH, SOD, CAT), inflammatory markers (MPO), calcium levels, and AChE activity.

The mean arterial blood pressure²², serum nitrite/nitrate (545nm)¹⁷, aortic superoxide anion (540nm)²³, brain total protien (750nm), TBARS (532nm)²², GSH (412nm)¹⁶, SOD (560nm)²⁴, CAT (240nm)²³, MPO (460nm)²⁴, AChE (420nm)²⁴, were estimated spectrophotometrically (UV-1800 ENG 240 V, Japan).

Statistical analysis:

The data is represented as mean ± S.D. The data was analyzed using one-way ANOVA (sigma stat 12.5) followed by Bonferroni’s post hoc test. The data for endothelial function was analyzed using repeated measures of ANOVA followed by Newman Keul’s test. The results were considered statistically significant when p < 0.05.

RESULTS:

Before conducting the psychological studies on MWM and ASST the animals were subjected to measure their motor coordination and locomotors activity. No significant difference was observed between 2K1C and 2K1C treated animals’ values during motor coordination and locomotor activity observation (data not shown). No significant differences were observed in drug per se and vehicle control groups on any of the parameters assessed. (data not shown)

Effect on MWM.

Sham control animals showed a significant decrease in day 4 ELT (compared to day 1 ELT), as well as significant increase in day 5 TSTQ as compared to other quadrants, depicting effective learning and memory. 2K1C animals as compared to sham control animals showed increased in day 4 ELT and decrease in day 5 TSTQ showing impairment of learning and memory. Administration of nicergoline (5 mg/kg or 10 mg/kg p.o.) or donepezil to 2K1C animals decreased the day 4 ELT as well as increased the day 5 TSTQ as compared to the 2K1C rats (Table 1).

Table 1: Effect of Nicergoline on escape latency time (ELT) and time spent in target quadrant (TSTQ), using Morris water maze (MWM).

Group	ELT		TSTQ
	D1	D4	D5
SC	95.34 ±6.17	42.27 ± 2.03^a	57.41 ± 1.99^d
CMC	94.16 ± 4.98	38.53 ± 2.71^a	58.34 ± 2.37^d
S	93.16 ± 5.19	40.59 ± 2.48^a	55.42 ± 2.73^d
NG5	93.33 ± 5.43	40.33 ± 2.97^a	59.29 ± 2.46^d
NG10	94.51 ± 6.03	40.16 ± 2.89^a	56.56 ± 2.73^d
D	96.63 ± 5.61	36.11 ± 2.15^a	57.29 ± 2.28^d
2K1C	96.33 ± 5.92	78.34 ± 2.31^b	28.45 ± 4.39^e
2K1C+NG5	95.37 ± 5.69	68.56 ± 2.94^c	41.43 ± 3.61^f
2K1C+NG10	92.43 ± 5.85	60.19 ± 2.68^c	48.26 ± 3.03^f
2K1C+D	96.32 ± 5.17	52.12 ± 2.51^c	50.19 ±2.93^f

Results are expressed as mean ± standard deviation (SD) and were statistically analyzed using one-way ANOVA followed by Bonferroni’s post-test

ELT: F (9, 50) =94.971; ^a p<0.05 vs day1 in respective group; ^bp<0.05 vs day 4 in control sham group. ^cp<0.05 vs day 4 in 2K1C group.

TSTQ: F (9, 50) =116.90; ^d p<0.05 vs mean time spent in other quadrant in respective group; ^e p<0.05 vs mean time spend in target quadrant by control sham group; ^fp<0.05 vs mean time spend in target quadrant by 2K1C group.

SC–Sham control; CMC- Carboxymethylcellulose; S- saline; NG5-Nicergoline 5mg/Kg; NG10-Nicergoline10mg/kg; D- Donepezil; 2K1C-Hypertention induction group.

Effect on reversal stage and extra- dimensional stage, using Attentional- set shifting

(ASST)

2K1C rats, in comparison to the sham control group showed increased number of trials during REV1 and ED stage of ASST signifying impairment in the reversal learning and executive functioning. Treatment with nicergoline (5 mg/kg or 10 mg/kg p.o.) or donepezil (0.5 mg kg-1, i.p.) daily attenuated 2K1C induced increase in number of trials during REV1 and ED stage indicating attenuation of 2K1C induced impairment in reversal learning and executive functioning (figure 1).

Fig.2. Effect on reversal stage and extra- dimensional stage, using Attentional- set shifting (ASST).

Results are expressed as mean ± standard deviation (SD) and were statistically analyzed using one-way ANOVA followed by Bonferroni’s post-test

RV 1- F (9, 50) =94.971; ^a p<0.05 vs control sham,^b P<0.05 vs 2K1C,

ED- F (10 55) =116.90; ^c p<0.05 vs control group; ^d p<0.05 vs 2K1C group

SC–Sham control; CMC- Carboxymethylcellulose; S- saline; NG5-Nicergoline 5mg/Kg; NG10-Nicergoline10mg/kg; D- Donepezil; 2K1C-Hypertention induction group.

Effect on endothelium dependent and independent relaxation:

Acetylcholine (ACh) and sodium nitroprusside (SNP) dose dependently produces endothelium dependent and independent relaxation in phenylephrine (3 × 10-6 M) precontracted isolated rat aortic ring preparation, respectively in sham control rats. 2K1C significantly attenuated ACh induced endothelium dependent relaxation, however, no affect was observed on the SNP induced endothelium independent relaxation. Treatment with nicergoline (5 mg/kg or 10 mg/kg p.o.) or donepezil (0.5 mg kg-1, i.p.) daily attenuated the effect of 2K1C on endothelial dependent relaxation. These interventions however, had no effect on the endothelium independent relaxation (figure 2).

Fig.2. Effect on endothelium-dependent relaxation.

Results are expressed as mean ± standard deviation (SD) one-way ANOVA followed by Newman-Keul’s test.

^a p<0.001Sham control group. ^bp<0.0012K1C group.

SC: Sham control; 2K1C: two-kidney-one-clip; NG: nicergoline; D: Donepezil;

Effect on mean arterial blood pressure, serum nitrite/nitrate, aortic superoxide anion and brain total protein, oxidative stress (TBARS, GSH, SOD, CAT), inflammatory markers (MPO), Calcium levels and AChE activity.

Compared to the sham control animals, 2K1C rats showed a decrease in serum nitrite/ nitrate along with increase in mean arterial blood pressure, aortic superoxide anion levels, as well as increase in brain oxidative stress (TBARS), inflammatory markers (MPO), calcium levels and AChE activity. Also, decreased in brain antioxidant markers (GSH, SOD, CAT) were observed in 2K1C rats in comparison to the sham control group. Treatment with nicergoline (5 mg/kg or 10 mg/kg p.o.) or donepezil (0.5 mg kg-1) significantly prevented 2K1C renovascular hypertension induced impairment in the serum, aortic and brain biochemicals (Table 2).

Table 2. Effect on serum nitrite/ nitrate, aortic superoxide anion, oxidative stress (TBARS, GSH, SOD, CAT), MPO, calcium levels, AChE activity.

Groups	Mean arterial blood pressure (mm Hg)		Serum Nitrite/Nitrate (µM/L)	Aortic superoxide anion production (reduced NBT pM/min/mg)	Brain TBARS (nM/mg protien)	Brain GSH (µM/mg of protein)
Groups	Basal	Final	Serum Nitrite/Nitrate (µM/L)		Brain TBARS (nM/mg protien)	Brain GSH (µM/mg of protein)
SC	90.6± 4.1	92±5.67^a	12.91±1.20	3.46±0.33	4.25±0.75	17.50±1.04
CMC	90.1± 3.92	89.8±5.23^a	13.91±1.02	3.66±0.32	4.08±0.58	17.50±1.04
S	89.1±4.8	88±5.17^a	12.91±1.28	3.73±0.37	3.91±0.91	17.33±1.21
NG5	90.6±4.72	90.3±5.39^a	13.58±0.91	3.46±0.45	4.0±0.70	17.16±1.16
NG10	87.1±3.94	87.5±5.41^a	13.58±1.02	3.48±0.44	4.0±0.89	16.93±0.99
D	89.3±3.39	90±5.09^a	13.91±1.20	3.68±0.31	4.5±1.04	17.08±0.80
2K1C	91.5±4.01	162.1±4.99^b	6.16±1.03^a	10.36±1.11^a	11.16±0.68^a	7.05±1.32^a
2K1C+NG5	88.3±4.23	151.3±5.19^c	8.15±0.74^b	8±0.89^b	9.50±0.44^b	10.0±0.89^b
2K1C+NG10	89.1±4.68	139.6±5.51^c	10.11±0.52^b	6.65±0.29^b	7.45±0.46^b	12.91±1.11^b
2K1C+D	91±4.81	157.8±4.33^c	12.08±0.58^b	4.78±0.18^b	5.58±0.58^b	15.33±0.60^b

Continew Table 2

Groups	Brain SOD (U/mg protein)	Braine Catalase Activity (U/mg protein)	Brain MPO (ugm/mg protein)	Brain Calcium (nM/mg of protein)	Brain AChE Activity (μM of ACh hydrolyzed/min/mg of protein)
Groups	Brain SOD (U/mg protein)	Braine Catalase Activity (U/mg protein)	Brain MPO (ugm/mg protein)	Brain Calcium (nM/mg of protein)
SC	85.16±6.11	6.86±0.62	0.0331±0.0047	64.33±3.26	4.50±1.04
CMC	84.0±5.93	7.18±0.73	0.0338±0.0061	64.66±2.5	3.66±1.21
S	83.16±5.49	7.1±060	0.0335±0.0053	64.33±3.44	3.83±0.98
NG5	83.66±4.63	7.13±0.52	0.0318±0.0043	64.33±2.73	4.33±0.81
NG10	83.66±4.45	7.20±0.59	0.0321±0.0049	62.5±3.45	4.33±0.81
D	83.66±2.94	6.93±0.51	0.0331±0.0050	63.66±4.27	3.83±1.16
2K1C	35.16±4.95^a	3.06±0.32^a	0.1616±0.0053^a	99.83±6.52^a	11.33±0.81^a
2K1C+NG5	48.83±2.78^b	4.10±0.36^b	0.14±0.0072^b	87.33±2.65^b	9.31±0.60^b
2K1C+NG10	60.83±3.48^b	5.20±0.47^b	0.1±0.0084^b	87.83±1.94^b	7.66±0.81^b
2K1C+D	73.33±2.73^b	6.33±0.45^b	0.0831±0.006^b	71±1.78^b	4.66±0.81^b

Results are mean ± standard deviation; One-way ANOVA followed by Bonferroni's post-test.

^a p < 0.001 versus control group; ^b p < 0.001 versus 2K1C group.

Mean arterial blood pressure- F (9,50) = 57.02; Serum nitrate/nitrite - F (9, 50) = 49.499; Aortic superoxide anion- F (9, 50) = 115.89; Brain TBARS- F (9, 50) = 72.758; Brain GSH- F (9, 50) = 69.603; Braine SOD- F (9, 50) = 115.89; Braine Catalase Activity- F (9, 50) = 49.994; Brain MPO- F (9, 50) = 429.32; Brain calcium- F (9, 50) = 77.235; Brain AChE Activity - F (9, 50) = 51.927;

SC–Sham control; CMC- Carboxymethylcellulose; S- saline; NG5-Nicergoline 5mg/Kg; NG10-Nicergoline 10mg/kg; D- Donepezil; 2K1C-Hypertention induction group.

DISCUSSION:

In present investigation, 2K1C increased mean arterial blood pressure, learning, memory (MWM), reversal memory, executive functioning (ASST) and impaired endothelial function in rats. 2K1C rats showed increased cerebral oxidative stress (↑TBARS, ↓GSH, ↓SOD, ↓CAT), MPO, and AChE activity. The results obtained are in accordance with the previously published result reports from ours as well as others’ lab. Further, treatment with nicergoline attenuated the behavioral deficits, endothelial dysfunction, and impaired biochemical parameters in 2K1C rats.

2K1C rats shows high blood pressure. This is maintained due to sympathetic drive, Na⁺/H₂O retention, and activation of the renin angiotensin system ²⁵. Continuous hypertension is characterized by rapid rise in the plasma renin levels which occurs due to decrease in renal arterial pressure and increase in circulating Ang I ²⁶. Circulating Ang II activates NF-kB signaling that potentiates increase in the blood pressure ²⁶. Hypertension has been known to exert serious adverse effects on the cognitive functions ^6,
16. Hypertension alters the molecular composition and structure of cerebral blood vessels that compromise the adequate supply of blood to the organ⁴. Hypertension impairs neuronal plasticity, learning, formation of memory, synthesis of protien, release of neurotransmitter as well as transmission of signals in the brain by decreasing the expression of endothelial nitric oxide synthetase (eNOS) and hence nitric oxide (NO) levels ²⁷. Reduction in the NO levels causes endothelial dysfunction, which itself is associated with memory deficits Hypertension also increases AChE activity, oxidative stress, inflammation and matrix metallo-protease activation ^28,29. Our previous studies have reported reduction in learning and memory due to endothelial dysfunction, increased oxidative stress, inflammation and AChE activity ^16-24,30. Therefore, in this study hypertension may have impaired learning, memory, reversal learning and executive functioning, via endothelial dysfunction, cholinergic dysfunction, oxidative stress and inflammation.

Endothelium maintains the balance between the vasoconstriction and vasodilation. Hypertension upregulates inducible nitric oxide synthase (iNOS) and downregulates endothelial nitric oxide synthetase (eNOS) expression²⁷ in the vessels that reduce NO dependent vasodilation ²⁸. Furthermore, hypertension increases vascular superoxide production and increase nicotinamide adenine dinucleotide phosphate (NADPH) oxidase ³¹. Increase in NADPH oxidase further increases reactive oxidation species (ROS) generation ³². Also, increase in the renin levels and circulating angiotensin-II have been known to increase oxidative stress and inflammatory status in hypertension by stimulating NADPH oxidase, TBARS, hydrogen peroxide, superoxide and interleukin and MPO levels ^33,34 as well as decrease anti-oxidant (GSH, SOD, CAT) and anti-inflammatory markers’ levels. Hence, increase in brain TBARS, MPO as well as decrease in brain SOD, GSH, and CAT have been previously observed in hypertensive rats ³⁵. Furthermore, oxidative stress and inflammation has been known to cause endothelial dysfunction and cognitive decline^36,37. Further, endothelial dysfunction, cholinergic dysfunction, inflammation and oxidative stress in 2K1C rats have resulted in cognitive dysfunction ^16-24.

Nicergoline administration in the present study reduces high blood pressure, possibly via inhibiting the central alpha 1-adrenoceptors, reducing the sympathetic tone, and increasing the vagal nerve activity ³⁸. Furthermore, Nicergoline has shown beneficial effects against impairment in learning, memory, attention and cognition during clinical and preclinical studies ^{9, 11}. Nicergoline prevents neuronal apoptosis and neuronal loss in the hippocampal cells as well as tissues. Nicergoline restores learning and memory in Alzheimer’s patients via inhibition of PI3K/AKT signaling pathway ¹¹. Administration of nicergoline provides beneficial effect against endothelial dysfunction, cholinergic dysfunction and oxidative stress^9,
12. Nicergoline suppresses superoxide anions and inflammatory markers production which results into neuroprotection³⁹. The increase in inflammation, oxidative stress, cholinergic dysfunction and endothelial dysfunction have already been reported to cause learning and memory impairment, in our previous studies ^{17, 22}. Therefore, beneficial effects of nicergoline on spatial memory, learning, reversal memory and executive functioning, observed in this study may have been due to its beneficial effect against endothelial dysfunction, oxidative stress, inflammation, and AChE activity.

Nicergoline administration in the current study increases the serum nitrite/nitrate levels. It is reported that, nicergoline increases nitric oxide synthase mRNA levels in the neurons¹³. Furthermore, treatment with nicergoline enhances the nerve growth factor production which regulates maintenance, growth, proliferation and survival of neurons¹³. Nicergoline interferes with Platelet aggregation and increases the cerebral blood flow via its vasodilator properties ⁴⁰. Nicergoline treatment significantly upregulates the intracellular anti-oxidants (GSH, SOD, CAT) and protects the cells against oxidative stress ⁴¹. Upregulation of anti-oxidants have shown beneficial effect against dementia and related conditions⁴². Administration of nicergoline lowers the brain lipid peroxidation that is TBARS as well as hydrogen peroxide levels ^{12, 41}. Nicergoline inhibits NF-kB and suppresses the production of superoxide anions, MPO, interleukin 1β, 6, and tumor necrosis factor- α ³⁹. Hence, nicergoline shows beneficial effects against reduced learning, memory, endothelial dysfunction, oxidative stress, inflammation, and AChE activity which, may be responsible for its effects against hypertension induced vascular endothelial dysfunction and related dementia.

Donepezil, a highly selective, potent, and reversible inhibitor of the AChE is a well-established drug for the management of memory dysfunction in AD patients ⁴³. Hence, donepezil was selected as a positive control in the present study.

Thus, we can conclude that, nicergoline provide beneficial effects by improving learning, memory, reversal memory, executive functioning, endothelial function, oxidative status, inflammation, and brain cholinergic activity in 2K1C hypertension induced endothelial dysfunction and related VaD. Furthermore, effect of nicergoline may be studied further to elucidate its full potential against hypertension induced vascular endothelial dysfunction and related dementia.

CONFLICT OF INTEREST:

No conflict of interest.

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Received on 12.12.2020 Modified on 17.04.2021

Research J. Pharm.and Tech 2021; 14(12):6669-6675.

DOI: 10.52711/0974-360X.2021.01152