|Year : 2012 | Volume
| Issue : 3 | Page : 366-371
Pharmacological investigation of memory restorative effect of riluzole in mice
Puneet Rinwa, Amteshwar Singh Jaggi, Nirmal Singh
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India
|Date of Submission||01-Aug-2011|
|Date of Decision||11-Dec-2011|
|Date of Acceptance||28-Feb-2012|
|Date of Web Publication||17-May-2012|
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab
Source of Support: None, Conflict of Interest: None
Objective: Streptozotocin (STZ) and sodium nitrite (NaNO 2 ) treatment have been positively correlated with higher incidence of memory loss and experimental dementia. The present study was designed to investigate the potential of the Riluzole, an inhibitor of glutamatergic neurotransmission and activator of TWIK-Related K + channels with incidences of memory deficits associated with dementia in mice.
Materials and Methods: Dementia was induced in Swiss albino mice by intracerebroventricular STZ (ICV) and by subcutaneous NaNO 2 in separate groups of animals. Morris water maze was employed to assess learning and memory of the animals. Biochemical analysis of brain homogenate was performed so as to assess brain acetyl cholinesterase (AChE) activity. Brain thiobarbituric acid reactive species (TBARS) levels and reduced glutathione (GSH) levels were measured to assess total oxidative stress.
Results: Treatment of ICV STZ and NaNO 2 produced a significant decrease in water maze performance of mice hence reflecting loss of learning and memory. Furthermore, higher levels of brain AChE activity and oxidative stress were observed in these animals. Administration of riluzole (5 and 10 mg/kg intraperitoneally) successfully attenuated memory deficits as well as ICV STZ- and NaNO 2 -induced changes in the levels of brain AChE, TBARS, and GSH.
Conclusion: The memory restorative effects of riluzole in dementia may involve its multiple functions including anti-oxidative and anticholinesterase properties.
Keywords: Riluzole, streptozotocin, dementia, TREK, morris water-maze
|How to cite this article:|
Rinwa P, Jaggi AS, Singh N. Pharmacological investigation of memory restorative effect of riluzole in mice. Indian J Pharmacol 2012;44:366-71
| » Introduction|| |
Dementia is an organic brain disorder clinically characterized by the development of multiple cognitive defects that are severe enough to interfere with daily social and professional functioning.  Alzheimer's disease (AD) is the most common cause of dementia in the elderly as according to World Health Organization, 5% of men and 6% of women aged above 60 years suffer from dementia of AD worldwide.  AD is basically a neurodegenerative disorder characterized by the progressive accumulation of amyloid beta peptide, neurofibrillary tangles, and hyperphosphorylated microtubule-associated tau protein. Today, there is no cure for this devastating disease and therefore it is of great interest for researchers to find novel drugs that can arrest the disease process. Drugs currently available in the market include inhibitors of acetyl cholinesterase (AChE) and N-methyl D-aspartate-receptor antagonists. These drugs improve the function of yet intact neurons, but do not inhibit the ongoing degenerative process leading to neuronal cell death. Scientists are currently exploring various targets/processes/agents which may provide relief and also stop the progression of dementia.
Riluzole, a 2-amino-6-(trifluoromethoxy) benzothiazole, is a well-known inhibitor of glutamatergic neurotransmission  and clinically important for its use in Amyotrophic Lateral Sclerosis. Riluzole is also known to modulate TWIK-Related K + (TREK) channels, the two-pore potassium (K + ) channel.  It is reported to exert potent anti-glutamate,  anticonvulsant,  anxiolytic,  anesthetic,  and anti-oxidative  actions. It has been observed to exert neuroprotective effect and prevent memory loss and hippocampal neuronal damage in ischemic gerbils.  It has also been shown to attenuate cognitive and neuromotor dysfunction associated with brain trauma in rats.  Although above reports clearly indicate the potential of riluzole in memory deficits associated with ischemic brain injury, little has been done to explore the memory preserving efficacy of riluzole in animal models of dementia. Furthermore, possible mechanism of action of riluzole in memory deficits also remains to be established. Therefore, the present study has been undertaken to investigate the ameliorative effect and possible mechanism of riluzole in memory deficit in mice.
| » Materials and Methods|| |
Swiss albino mice (12 weeks old) (procured from CRI, Kasauli) of either sex weighing 20 to 25 g were employed in the present study. They were maintained on standard laboratory pellet chow diet (Kisan Feeds Ltd, Chandigarh, India) and water ad libitum. The animals were exposed to natural light and dark cycles. The mice were acclimatized to the laboratory conditions five days prior to the behavioral study. The protocol of study was duly approved by Institutional Animal Ethics Committee and care of the animals was carried out as per the guidelines of Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environment and Forest, Government of India (Reg. No. 107/1999/CPCSEA).
Drugs and Chemicals
All the drug solutions were freshly prepared before use. Riluzole was obtained as a gift sample from Sun Pharmaceuticals Ind. Ltd, Mumbai. Streptozotocin (STZ) was purchased from Sigma-Aldrich, St. Louis USA. 5, 5, dithiobis (2-nitro benzoic acid), reduced glutathione (GSH), Bovine serum albumin, thiobarbituric acid, and Sodium Nitrite (NaNO 2 ) were obtained from Loba Chem, Mumbai, India. Riluzole was suspended in 0.5% w/v sodium carboxymethyl cellulose (CMC). STZ was dissolved in artificial cerebrospinal fluid (ACSF).  ACSF was freshly prepared (147 mM NaCl; 2.9 mM KCl; 1.6 mM Mgcl 2 ; 1.7 mM dextrose). Riluzole was administered intraperitoneally (i.p.) and NaNO 2 was administered subcutaneously (s.c.). STZ and ACSF were delivered intracerebroventricularly (ICV).
| » Laboratory Models|| |
Exteroceptive Behavioral Model
water-maze (MWM) test was employed to assess learning and memory of the animals.  MWM is a swimming-based model where the animal learns to escape on to a hidden platform. It consists of a large circular pool (150 cm in diameter, 45 cm in height, filled to a depth of 30 cm with water at 28 ± 1°C). The water was made opaque with white-colored non-toxic dye. The tank is divided into four equal quadrants with the help of two threads, fixed at right angle to each other on the rim of the pool. A submerged platform (10 cm²), painted in white, is placed inside the target quadrant of this pool, 1 cm below surface of water. The position of the platform is kept unaltered throughout the training session. Using this, each animal was subjected to four consecutive training trials on each day with inter-trial gap of 5 minutes. The mouse was gently placed in the water between quadrants, facing the wall of pool with drop location changing for each trial, and allowed 120 seconds to locate submerged platform. Then, it was allowed to stay on the platform for 20 seconds. If it failed to find the platform within 120 seconds, it was guided gently onto platform and allowed to remain there for 20 seconds. Mean escape latency time (ELT), i.e., the time taken to locate the hidden platform in water maze, was noted and Day 4 mean ELT taken as an index of acquisition or learning. Animal was subjected to training trials for four consecutive days, the starting position was changed with each exposure as mentioned below and target quadrant (Q 4) remained constant throughout the training period.
On fifth day, platform was removed and each mouse was allowed to explore the pool for 120 seconds. Mean time spent in all four quadrants was noted. The mean time spent by the animal in target quadrant (TSTQ) searching for the hidden platform was noted as index of retrieval. The MWM data were recorded manually with the help a digital instrument consisting of a set of four stop watches and the experimenter always stood at the same position. Care was taken that relative location of water maze with respect to other objects in the laboratory, serving as prominent visual clues were not disturbed during the total duration of study. All the trials were completed between 09.00 to 17.00 hours.
Interoceptive Behavioral Models
These included the following:
Intracerebroventricular streptozotocin-induced dementia
- STZ-induced dementia
- Sodium nitrite-induced dementia
STZ was administered ICV to induce experimental dementia. Mice were anesthetized with anesthetic ether for ICV administrations. Ether has been preferred here due to its ultrashort action and fast reversibility. Moreover, brief extent of ether exposure for ICV injection has been reported to exert no significant effect on learning and memory behavior of animal.  ICV injections were made with hypodermic needle of 0.4 mm external diameter attached to a 10-μl Hamilton microliter syringe (Top Syringe, Mumbai, India). The needle was covered with a polypropylene tube except 3 mm of the tip region so as to insert this much portion of the needle perpendicularly through the skull into the brain of mouse. STZ was dissolved in ACSF (25 mg/ml) solution, made freshly. The injection site was 1 mm to right or left midpoint on the line drawn through to the anterior base of the ears. Injections were performed into right or left ventricle randomly. Two doses of STZ (3 mg/kg) were administered by ICV injection bilaterally. The second dose was administered after 48 hours of first dose. The concentration was adjusted so as to deliver 10 μl in an injection. Control group mice were given ICV injection of ACSF (147 mM NaCl; 2.9 mM KCl; 1.6 mM Mgcl 2 ; 1.7 mM dextrose) in a similar manner.
Sodium nitrite-induced dementia
NaNO 2 (75 mg/kg) was administered s.c. prior to acquisition trial to induce memory loss. 
| » Collection of Samples|| |
Blood samples were taken by retro orbital puncture, the animals were then sacrificed by cervical dislocation; brains were removed and homogenized in phosphate buffer (pH = 7.4). The homogenates were than centrifuged at 3 000 rpm for 15 minutes. The supernatant of homogenate was used for biochemical estimations (i.e., brain AChE, thiobarbituric acid reactive species [TBARS], and GSH).
| » Estimation of Brain Acetyl Cholinesterase Activity|| |
The whole brain AChE activity was measured by the method of Ellman et al.  with slight modifications. Change in absorbance per min. of the sample was read spectrophotometrically (DU 640B spectrophotometer, Beckman Coulter Inc., CA, USA) at 420 nm.
| » Estimation of Brain Thiobarbituric Acid Reactive Species Level|| |
The whole brain TBARS level was measured by the method of Ohkawa et al.  with slight modifications. The absorbance was measured spectrophotometrically at 532 nm.
| » Estimation of Brain Glutathione Level|| |
The whole brain GSH level was measured by the method of Beutler et al.  with slight modifications. The absorbance was measured spectrophotometrically at 412 nm.
| » Experimental Protocol|| |
Ten groups of mice were employed in the present study and each group comprised of eight mice. The groups were run individually over the time.
Group I (control)
Mice were administered distilled water (1 ml/kg s.c.) 30 minutes before acquisition trials conducted from day1 to day 4 and 30 minutes before retrieval trial conducted on day 5.
Group II (carboxymethyl cellulose control)
Mice were administered CMC (0.5% w/v, 10 ml/kg i.p.) 30 minutes before acquisition trials conducted from day 1 to day 4 and 30 minutes before retrieval trial conducted on day 5.
Group III (sodium nitrite)
Mice were injected NaNO 2 (75 mg/kg s.c.) 30 minutes before acquisition trials conducted from day 1 to day 4 and vehicle (distilled water) 30 minutes before retrieval trial conducted on day 5.
Group IV (artificial cerebrospinal fluid control)
Mice were injected ICV ACSF (25 mg/ml, 10 μl) in two dosage schedules, i.e., on first and third day followed by exposure to MWM test after 14 days.
Group V (intracerebroventricular streptozotocin)
Mice were injected STZ (3 mg/kg, 10 μl) in two dosage schedules, i.e., on first and third day followed by exposure to MWM test after 14 days.
Group VI (riluzole per se)
Mice were treated with riluzole (10 mg/kg i.p.) 30 minutes before acquisition trials conducted from day 1 to day 4 and vehicle (CMC 0.5% w/v, 10 ml/kg i.p.) 30 minutes before retrieval trial conducted on day 5.
Group VII (low-dose riluzole + sodium nitrite)
Mice were treated with riluzole (5 mg/kg i.p.), 30 minutes before NaNO 2 treatment (75 mg/kg s.c.) and rest of the procedure was same as mentioned in group III.
Group VIII (high-dose riluzole + sodium nitrite)
Mice were treated with riluzole (10 mg/kg i.p.), 30 minutes before NaNO 2 treatment (75 mg/kg s.c.) and rest of the procedure was same as mentioned in group III.
Group IX (intracerebroventricularly streptozotocin + low-dose riluzole)
ICV STZ mice were treated with riluzole (5 mg/kg i.p.) for 14 days (starting after second dose of STZ) and then subjected to MWM test. The administration of riluzole was continued (administered 30 minutes before) during acquisition trial conducted from day 1 to day 4. The animals were administered vehicle (0.5% w/v CMC, 10 ml/kg i.p.) only, given 30 minutes before retrieval trial conducted on day 5.
Group X (intracerebroventricularly streptozotocin + high-dose riluzole)
ICV STZ mice were treated with riluzole (10 mg/kg i.p.) for 14 days (starting after second dose of STZ) and rest of the procedure was same as mentioned for group IX.
The results were expressed as mean ± standard error of means (S.E.M). The data obtained from various groups were statistically analyzed using one-way ANOVA followed by Tukey's Multiple Range test. P<0.05 was considered to be statistically significant.
| » Results|| |
Effect of Vehicles on Escape Latency Time and Time Spent in Target Quadrant Using Morris Water Maze
Control (Distilled water) mice showed a downward trend in their ELT on subsequent exposure to MWM. There was a significant fall in day 4 ELT of control mice as compared with their day 1 ELT, reflecting normal learning ability [Table 1]. Furthermore, these animals showed a significant rise in day 5 TSTQ, when compared with time spent in other quadrants during retrieval trial conducted on day 5, thus reflecting normal retrieval (memory) as well. Administration of vehicles, i.e., CMC and ACSF did not show any significant effect of day 4 ELT [Table 1] and day 5 TSTQ of control animals [Figure 1].
|Figure 1: Effect on time spent in target Quadrant using Morris Water Maze SN=Sodium nitrite, STZ=Streptozotocin, ACSF=Artificial cerebrospinal fluid, Rlz=Riluzole, Low-dose Riluzole=5mg kg-1, Highdose Riluzole=10mg kg-1. Each group (n=8) represents mean±S.E.M. adenotes P<0.05 vs time spent in other quadrants of Control group,|
bdenotes P<0.05 vs TSTQ of control group, cdenotes P<0.05 vs TSTQ of STZ group, ddenotes P<0.05 vs TSTQ of STZ + Riluzole group
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Effect of Streptozotocin (ICV) and Sodium Nitrite (s.c.) on Escape Latency Time and Time Spent in Target Quadrant Using Morris Water Maze
STZ (ICV)- as well as NaNO 2 (s.c.)-treated mice showed a significant increase in day 4 ELT, when compared with day 4 ELT of control, indicating impairment of acquisition [Table 1]. Furthermore, a significant decrease in day 5 TSTQ of these animals was also noted reflecting impairment of memory as well [Figure 1].
Effect of Riluzole on Streptozotocin and Sodium Nitrite-induced Impairment of Learning and Memory Using Morris Water Maze
Treatment with riluzole prevented STZ as well as NaNO 2 -induced rise in day 4 ELT [Table 1] and fall in day 5 TSTQ [Figure 1] in a dose-dependent manner. However, administration of riluzole did not show any significant per se effect on day 4 ELT [Table 1] and day 5 TSTQ [Figure 1].
Effect of Riluzole on Streptozotocin and Sodium Nitrite-induced Changes in Brain Acetyl Cholinesterase Activity
Administration of ICV STZ as well as NaNO 2 (s.c.) showed a significant increase in brain AChE activity in mice as compared with control [Figure 2]. While treatment with riluzole significantly prevented ICV STZ and NaNO 2 induced rise in brain AChE activity in a dose-dependent manner [Figure 2]. However, administration of riluzole did not show any significant per se effect on brain AChE activity [Figure 2].
|Figure 2: Effect on brain acetylcholinesterase (AChE) activity SN=Sodium nitrite, STZ=Streptozotocin, ACSF=Artificial cerebrospinal fluid, Rlz=Riluzole, Low-dose Riluzole=5 mg/kg, High-dose Riluzole=10 mg/kg. Each group (n=8) represents mean±S.E.M. adenotes P<0.05 vs control group, bdenotes P<0.05 vs SN group, cdenotes P<0.05 vs STZ group|
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Effect of Riluzole on Streptozotocin and Sodium Nitrite-induced Changes in Oxidative Stress Levels of Brain
STZ as well as NaNO2 treatment showed a significant increase in brain oxidative stress levels manifested in terms of increased TBARS level [Figure 3] and decreased reduced form of GSH level [Figure 4], when compared with control. Treatment with riluzole significantly and dose dependently reduced the STZ and NaNO2 -induced rise in brain oxidative stress levels [Figure 3] and [Figure 4]. However, administration of riluzole did not show any significant per se effect on brain oxidative stress levels [Figure 3] and [Figure 4].
|Figure 3: Effect on brain thiobarbituric acid reactive species (TBARS) levels SN=Sodium nitrite, STZ=Streptozotocin, ACSF=Artificial cerebrospinal fluid, Rlz=Riluzole, Low-dose Riluzole=5 mg/kg, Highdose Riluzole=10 mg/kg. Each group (n=8) represents mean±S.E.M. adenotes P<0.05 vs control group, bdenotes P<0.05 vs SN group, cdenotes P<0.05 vs STZ group|
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|Figure 4: Effect on brain reduced glutathione (GSH) levels SN=Sodium nitrite, STZ=Streptozotocin, ACSF=Artificial cerebrospinal fluid, Rlz=Riluzole, Low-dose Riluzole=5 mg/kg, High-dose Riluzole=10 mg/ kg. Each group (n=8) represents mean±S.E.M. adenotes P<0.05 vs control group, bdenotes P<0.05 vs SN group,|
cdenotes P<0.05 vs STZ group
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| » Discussion|| |
MWM test employed in the present study is one of the most widely accepted models to evaluate learning and memory of the animals.  A significant decrease in day 4 ELT of control animals during ongoing acquisition trials denoted normal acquisition of memory and an increase in TSTQ, in search of missing platform during retrieval trial indicated, retrieval of memory. Animals of both sexes have been employed in this study; the idea was to observe the effect of drug not only in males but in animals of both sexes. The fact that estrogen is known to improve memory is taken care by equally distributing the male and female mice in all groups, including that of control.
In our study, ICV STZ not only impaired learning and memory of mice but also produced a significant rise in brain AChE activity as well as oxidative stress (increase in TBARS and decrease in GSH) levels. STZ (ICV) model has been described as an appropriate animal model for dementia, typically characterized by progressive impairment of learning abilities and memory capacities.  Significant memory loss was seen after two weeks of second dose of ICV STZ. Cerebral glucose and energy metabolism is associated with oxidative stress. After ICV administration, the highest concentration of STZ (3 mg/kg) reaches the fornix and periventricular white matter at the level of third ventricle, which show the greatest damage and ICV STZ-induced dementia is independent of its hyperglycemic effect.  Although the mechanism of action of ICV STZ on memory impairment is not yet known, it probably involves the induction of oxidative stress  to which myelin is particularly vulnerable. Damage to myelin by oxidative stress is seen in disorders such as AD with cognitive impairment.  In addition, reduced energy metabolism and synthesis of acetyl-CoA ultimately results in cholinergic deficiency and thereby memory deficit in ICV STZ rats.
Similar to that of ICV STZ, NaNO 2 (s.c.) treatment in the present investigation also resulted in significant loss of memory along with rise in brain oxidative stress (i.e., increase in TBARS and decrease in GSH) levels and brain AChE activity. NaNO 2 has been used to induce chemical hypoxia and associated memory loss in animals and is a good model of experimental dementia.  Basically, by virtue of its chemical nature, NaNO 2 produces methemoglobinemia eventually leading to cerebral hypoxia.  Administration of NaNO 2 at dose of 75 mg/kg (s.c.) has been reported to produce significant impairment of learning and memory in animals.  However, in contrast to ICV STZ, memory loss induced by NaNO 2 is acute in nature. One of the most serious consequences of hypoxia/ischemia in human beings is a decline of memory and ability to learn and acquire novel experiences. Cerebral hypoxia/ischemia occurring with environmental limitations, insufficient blood flow, respiratory dysfunction, the use of some toxic chemical/substance or during aging have been demonstrated to result in a high incidence of memory deficits.  Furthermore, it has been observed that ischemia/hypoxia leads to an increase in extracellular excitatory amino acid concentrations resulting in glutamate receptor-mediated excitotoxic events.  During hypoxia, increased synaptic release and impaired cellular re-uptake of glutamate results in large increases in extracellular glutamate eventually leading to neurodegeneration and dementia. 
In the present study, riluzole has significantly reversed STZ as well as NaNO 2 -induced memory deficits, manifested in the terms of increase in MWM performance. Riluzole was administered for 14+4=18 days to STZ animals because STZ-treated mice show a persistent memory deficit in MWM test after 14 days of the second dose; hence, a prolonged treatment with riluzole is required. On the other hand, NaNO 2 -treated mice show early memory loss; hence, riluzole was administered for 4 days to these mice. Riluzole treatment also produced a significant decrease in brain AChE activity and oxidative stress (decrease in TBARS and increase in GSH) levels. Riluzole as mentioned earlier possesses potent neuroprotective, , anti-glutamate, and anti-oxidative actions.  Therefore, it looks evident that riluzole in this study alleviated STZ as well as NaNO 2 -induced memory deficits by virtue of its above mentioned effects. Furthermore, observed inhibition of brain AChE activity with riluzole might also have played a significant role. Moreover, at this point, riluzole induced modulation of TREK channels, the two-pore potassium (K + ) channel can also not be ruled out.
TREK-1 (also known as KCNK2) is a member of the most recently discovered family of two-pore-domain K + channels, so called because they contain two pore-forming domains in their primary sequence. The class of mammalian two-pore-domain K + channel subunits now includes 15 members, which are thought to dimerize to form functional channels. Human TREK-1 channels are highly expressed in many regions of the central nervous system such as prefrontal cortex, hippocampus, hypothalamus, midbrain serotonergic neurons of the dorsal raphe nucleus, and in sensory neurons of dorsal root ganglia and are generally believed to play a critical role in controlling neuronal excitability.  A remarkable feature of the TREK-1 channel is its sensitivity to a wide variety of endogenous and exogenous modulators.  It has been well documented that under conditions of hypoxia, TREK-1 becomes insensitive.  Neuroprotective riluzole has been demonstrated to activate TREK-1.  Recent study has also documented that TREK-1 play an important role in learning and memory processes.  Therefore, it may be speculated that hypoxia induced due to administration of NaNO 2 led to insensitivity of TREK-1 channels with subsequent memory loss, this effect was abolished by our pretreatment of riluzole, a neuroprotective and an activator of TREK-1 channels. 
| » Conclusion|| |
It may be concluded that beneficial effect of riluzole in dementia may involve its multiple effects including anti-oxidative and anticholinesterase actions. Nevertheless, further studies are needed to elucidate the full potential and mechanism of riluzole as memory restorative agent with special focus on TREK-1 channels.
| » Acknowledgments|| |
The authors would like to acknowledge Department of Pharmaceutical Sciences and Drug Research, Punjab University, Patiala for providing technical facilities.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
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