Spinal cord stimulation in experimental chronic painful diabetic polyneuropathy: Delayed effect of High-frequency stimulation.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to provide pain relief in painful diabetic polyneuropathy (PDPN). As the vasculature system plays a great role in the pathophysiology of PDPN, a potential beneficial side-effect of SCS is peripheral vasodilation, with high frequency (HF) SCS in particular. We hypothesize that HF-SCS (500 Hz), compared with conventional (CON) or low frequency (LF)-SCS will result in increased alleviation of mechanical hypersensitivity in chronic experimental PDPN. METHODS: Diabetes was induced in 8-week-old female Sprague-Dawley rats with an intraperitoneal injection of 65 mg/kg of streptozotocin (n = 44). Rats with a significant decrease in mechanical withdrawal response to von Frey filaments over a period of 20 weeks were implanted with SCS electrodes (n = 18). Rats were assigned to a cross-over design with a random order of LF-, CON-, HF- and sham SCS and mechanical withdrawal thresholds were assessed with von Frey testing. RESULTS: Compared with sham treatment, the average 50% WT score for 5 Hz was 4.88 g higher during stimulation (p = 0.156), and 1.77 g higher post-stimulation (p = 0.008). CON-SCS resulted in 50% WT scores 5.7 g, and 2.51 g higher during (p = 0.064) and after stimulation (p < 0.004), respectively. HF-SCS started out with an average difference in 50% WT score compared with sham of 1.87 g during stimulation (p = 0.279), and subsequently the steepest rise to a difference of 5.47 g post-stimulation (p < 0.001). CONCLUSIONS: We demonstrated a delayed effect of HF-SCS on mechanical hypersensitivity in chronic PDPN animals compared with LF-, or CON-SCS. SIGNIFICANCE: This study evaluates the effect of SCS frequency (5-500 Hz) on mechanical hypersensitivity in the chronic phase of experimental PDPN. High frequency (500 Hz) - SCS resulted in a delayed effect- on pain-related behavioural outcome in chronic PDPN.

Neonatal paracetamol treatment reduces long-term nociceptive behaviour after neonatal procedural pain in rats.

BACKGROUND: Pain from skin penetrating procedures (procedural pain) during infancy in the neonatal intensive care unit (NICU) may result in changes of nociceptive sensitivity in later life. This supports the need for pain management during such vulnerable periods in life. This study, therefore, analyses the short- and long-term consequences of neonatal paracetamol (acetaminophen) treatment on pain behaviour in an experimental rat model of neonatal procedural pain. METHODS: A repetitive needle-prick model was used, in which neonatal rats received four needle pricks into the left hind paw per day from postnatal day 0 to day 7 (P0-P7). Paracetamol (50 mg/kg/day s.c.) was administered daily (P0-P7), and sensitivity to mechanical stimuli was compared with a needle-prick/saline-treated group and to a tactile control group. At 8 weeks of age, all animals underwent an ipsilateral paw-incision, modelling postoperative pain, and the duration of hypersensitivity was assessed. RESULTS: Neonatal paracetamol administration had no effect upon short-term mechanical hypersensitivity during the first postnatal week or upon long-term baseline sensitivity from 3 to 8 weeks. However, neonatal paracetamol administration significantly reduced the postoperative mechanical hypersensitivity in young adults, caused by repetitive needle pricking. CONCLUSION: Paracetamol administration during neonatal procedural pain does not alter short-term or long-term effects on mechanical sensitivity, but does reduce the duration of increased postoperative mechanical hypersensitivity in a clinically relevant neonatal procedural pain model. WHAT DOES THIS STUDY ADD: Paracetamol can be used safely in neonatal rats. Neonatal paracetamol treatment had no effect upon short-term mechanical hypersensitivity during the first postnatal week, nor upon long-term baseline sensitivity from 3 to 8 weeks. Paracetamol treatment during the first postnatal week significantly reduced the postoperative mechanical hypersensitivity in young adult rats.

The effect of spinal cord stimulation frequency in experimental painful diabetic polyneuropathy.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to be an effective treatment for painful diabetic polyneuropathy (PDP). An increase of efficacy is needed since only 67% of patients benefit from SCS. This study aimed to develop an animal model for SCS in PDP and study the effect of various stimulation frequencies on the functional outcome. As the pathophysiology of PDP is complex, including vasoconstriction and nerve injury, the frequency of SCS may result in different outcomes. METHODS: Diabetes mellitus was induced by an intraperitoneal injection of streptozotocin in 8-week-old female Sprague-Dawley rats (n=76; glucose >15 mmol/L; n=51). A SCS device was implanted at level Th13 4 weeks later. SCS of the dorsal columns was applied for 30 min and the effect on mechanical hypersensitivity was evaluated. RESULTS: Mechanical hypersensitivity developed in 26 rats, which were included (low-frequency, n=6; mid-frequency, n=8; high frequency, n=9; and sham, n=3). SCS of the dorsal columns was applied for 40 min, and the effect on mechanical hypersensitivity was evaluated. In all treatment groups, SCS resulted in reversal of mechanical hypersensitivity and a clinically relevant reduction was achieved in 70% of animals. No differences in efficacy were found between the different treatment groups. CONCLUSIONS: The pain-relieving effect of SCS in PDP was studied in an experimental model. Our study shows that SCS on mechanical hypersensitivity in PDP rats is equally effective when applied at low, mid and high frequency.

The CatWalk method: a detailed analysis of behavioral changes after acute inflammatory pain in the rat.

Experimental pain research is often complicated by the absence of an objective and detailed method to analyze behavioral changes. In the present study, acute pain was induced into the right knee of the rat (n=15) through the injection of 2mg carrageenan (CAR) in saline. A control group received vehicle injection into the knee (n=15). With the use of an automated quantitative gait analysis system, the CatWalk, it was possible to quantitatively analyze behavioral changes at post-injection time 2.5, 4, 24 and 48h. The CatWalk analysis of individual paw parameters like the intensity of the paw print or the time contact with the floor showed a significant effect after CAR injection into the knee. These CatWalk parameters were highly correlated with von Frey data and thus representative for the development of mechanical allodynia. Furthermore, detailed CatWalk analysis of the gait (i.e. coordinated interaction between left and right hindlimb) showed very fine, accurate and significant coordination changes in the experimental rats from 4h post-injection. In conclusion, the CatWalk method allows an objective and detailed detection of both pain-induced gait adaptations as well as the development of mechanical allodynia in an acute inflammatory pain model.

Effect of spinal cord stimulation in an animal model of neuropathic pain relates to degree of tactile "allodynia".

Spinal cord stimulation (SCS) is an established treatment for chronic neuropathic pain. However, in recent studies conflicting results regarding the effect of SCS were noted in a selected group of patients suffering from complex regional pain syndrome and mechanical allodynia. In the present study we investigated the pain relieving effect of SCS in a rat experimental model of neuropathic pain as related to the severity of mechanical allodynia. Adult male rats (n=45) were submitted to a unilateral sciatic nerve ligation. The level of allodynia was tested using the withdrawal response to tactile stimuli with the von Frey test. A portion of these rats developed marked tactile hypersensitivity in the nerve-lesioned paw (von Frey test), similar to "tactile allodynia" observed after nerve injury in humans. Prior to SCS treatment the rats were subdivided into three groups based on the level of allodynia: mild, moderate and severe. All allodynic rats were treated with SCS (n=27) for 30 min (f=50 Hz; pulse width 0.2 ms and stimulation at 2/3 of motor threshold) at 16 days post-injury. Our data demonstrate a differential effect of SCS related to the severity of the mechanical allodynia. SCS leads to a faster and better pain relief in mildly allodynic rats as compared with the more severely allodynic rats. Thus, we suggest that the selection and subdivision of patient groups similar to those defined in our experimental setting (mild, moderate and severe allodynic) may provide better pre-treatment prediction of possible therapeutic benefits of SCS.

Olfactory ensheathing cells, olfactory nerve fibroblasts and biomatrices to promote long-distance axon regrowth and functional recovery in the dorsally hemisected adult rat spinal cord.

Cellular transplantation, including olfactory ensheathing cells (OEC) and olfactory nerve fibroblasts (ONF), after experimental spinal cord injury in the rat has previously resulted in regrowth of severed corticospinal (CS) axons across small lesion gaps and partial functional recovery. In order to stimulate CS axon regrowth across large lesion gaps, we used a multifactorial transplantation strategy to create an OEC/ONF continuum in spinal cords with a 2-mm-long dorsal hemisection lesion gap. This strategy involved the use of aligned OEC/ONF-poly(D,L)-lactide biomatrix bridges within the lesion gap and OEC/ONF injections at 1 mm rostral and caudal to the lesion gap. In order to test the effects of this complete strategy, control animals only received injections with culture medium rostral and caudal to the lesion gap. Anatomically, our multifactorial intervention resulted in an enhanced presence of injured CS axons directly rostral to the lesion gap (65.0 +/- 12.8% in transplanted animals versus 13.1 +/- 3.9% in control animals). No regrowth of these axons was observed through the lesion site, which may be related to a lack of OEC/ONF survival on the biomatrices. Furthermore, a 10-fold increase of neurofilament-positive axon ingrowth into the lesion site as compared to untreated control animals was observed. With the use of quantitative gait analysis, a modest recovery in stride length and swing speed of the hind limbs was observed. Although multifactorial strategies may be needed to stimulate repair of large spinal lesion gaps, we conclude that the combined use of OEC/ONF and poly(D,L)-lactide biomatrices is rather limited.

Chronically injured corticospinal axons do not cross large spinal lesion gaps after a multifactorial transplantation strategy using olfactory ensheathing cell/olfactory nerve fibroblast-biomatrix bridges.

Transplantation of mixed cultures containing olfactory ensheathing cell (OEC) and olfactory nerve fibroblasts (ONF) has been shown to stimulate regrowth of both acutely and chronically injured corticospinal (CS) axons across small spinal cord lesion gaps. Here, we used a multifactorial transplantation strategy to stimulate regrowth of chronically injured CS axons across large spinal cord lesion gaps. This strategy combined the transplantation of aligned OEC/ONF-biomatrix complexes, as described previously (Deumens et al. [2004] Neuroscience 125:591-604), within the lesion gap with additional OEC/ONF injections rostral and caudal to the lesion site. We show an enhanced presence of injured CS axons directly rostral to the lesion gap, with no effects on injured CS axons at or caudal to the lesion gap. Furthermore, injured CS axons did not penetrate the OEC/ONF-biomatrix complex within the lesion gap. The enhanced presence of CS axons rostral to the lesion gap was not accompanied by any recovery of behavioral parameters assessed with the BBB locomotor rating scale or CatWalk gait analysis. We conclude that our multifactorial transplantation strategy should be optimized to create an OEC/ONF continuum in the injured spinal cord and thereby stimulate regrowth of injured CS axons across large spinal lesion gaps.

Alignment of glial cells stimulates directional neurite growth of CNS neurons in vitro.

Olfactory ensheathing cells (OECs) together with olfactory nerve fibroblasts (ONFs) and neonatal astrocytes are potent stimulators of neurite growth in adulthood and during development, respectively. Since it is known that alignment of glial cells is important for the correct outgrowth of axon tracts, it was hypothesized that the alignment of glial cells stimulates directional and enhanced neurite outgrowth. Adult OEC/ONF and neonatal astrocytes were cultured either on biodegradable poly(d,l)-lactide matrices or in Petri dishes for 4 days. Thereafter neonatal cerebral cortical neurons were added. After a 2-days coculture period the cultures were fixed and processed for a combined MAP-2 and phosphorylated neurofilament (RT97) staining. The neurite growth (neurite elongation and neurite formation) and the neurite direction were assessed. We show that (1). OEC/ONF cultures are more potent in stimulating the length of the longest neurite of cocultured neurons, (2). alignment of glial is achieved in vitro on our biomatrices, (3). aligned glial/biomatrix complexes do not enhance neurite growth, and (4). aligned glial/biomatrix complexes direct neurite outgrowth. These data have significant implications for in vivo experiments focusing on glial transplantation. Transplanting glial/biomatrix complexes may stimulate the directional regrowth of severed axons across a lesion site.

Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood-brain barrier during aging.

SUMMARY: The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57Bl/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57Bl/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease.

Long-term consequences of repeated pentobarbital anaesthesia on choice reaction time performance in ageing rats.

Recent studies have suggested that anaesthesia may be a factor in cognitive decline with age. We examined the effect of repeated (eight times) anaesthesia with pentobarbital on reaction time performance in rats in a longitudinal study. Treated rats had faster response times and made more premature responses than the control rats when they were older than 21 months. The results suggest that repeated anaesthesia during the lifespan can lead to an increase in impulsivity, as assessed by a choice reaction time test, during the later stages of life in the rat. These findings support the theory that repeated anaesthesia is a biological factor that affects cognitive ageing.

Nitric oxide synthase does not mediate neurotoxicity after an i.c.v. injection of streptozotocin in the rat.

In the present study we evaluated the possible role of nitric oxide (NO) in mediating neuronal damage in middle-aged rats after an i.c.v. injection of streptozotocin (STREP). An i.c.v. injection of STREP has been reported to decrease the central metabolism of glucose. This inhibition of the energy metabolism after STREP treatment might induce an excitotoxic mechanism, which may lead to the stimulation of NO synthase and, consequently to the synthesis of NO. On the other hand, STREP might induce oxidative stress directly by liberation of NO from its nitroso moiety. To investigate whether NO synthase is involved in a possible excitotoxic mechanism after STREP treatment, some of the rats treated with STREP (1.25 mg/ kg in 4 microl, bilaterally 2 microl/injection site) were also treated with the NO synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg i.p. 10 min, 6, 24 and 96 h after STREP injection). To investigate whether NO liberated from STREP may be responsible for neurotoxic effects, one additional group of control rats received an i.c.v. injection of the NO donor sodium nitroprusside (SNP, 10 microg in 4 microl). We found that STREP affected the behavioral performances in the open field and two-way active avoidance task. In addition, immunostaining for glial fibrillary acidic protein, an indicator of reactive astroglial changes to neuronal damage, showed that this was mainly located in peri- and paraventricular regions of the third and lateral ventricles, like for instance in the septum, caudate putamen and hippocampus. L-NAME treatment had no protective effect on the behavioral impairments and neuronal damage of STREP-treated rats. This suggests that the neuronal damage of STREP may still be a result of the decrease in the central energy metabolism, but without the involvement of NO synthase. This was supported by measuring, using immunostaining, the NO-mediated cyclic GMP production by the enzyme soluble guanylyl cyclase in cortical slices, i.e. L-NAME did not prevent NO production after STREP administration in vitro. In addition, it was found that SNP liberated NO in vitro, whereas in vivo SNP administration did not lead to any behavioral and neuronal deficits at all. However, the present study cannot exclude the involvement of NO liberated from STREP in neuronal damage.

Metrifonate improves working but not reference memory performance in a spatial cone field task.

The effects of metrifonate (3, 10 and 30 mg/kg, p.o.) on the working and reference memory performance of the rat were assessed in a spatial cone field task. The highest dose of metrifonate (30 mg/kg) improved the working memory performance, whereas none of the doses affected the reference memory performance. Other parameters of spatial discrimination performance were not affected by metrifonate treatment. The present results suggest that metrifonate has cognition-enhancing properties which are likely to be related to aspects of (spatial) working memory.

Cognition-enhancing properties of subchronic phosphatidylserine (PS) treatment in middle-aged rats: comparison of bovine cortex PS with egg PS and soybean PS.

There are various clinical and non-clinical studies that have indicated that phosphatidylserine (PS) treatment can improve cognitive functions in humans and other animals. However, treatment with PS derived from bovine cortex is not desirable because of possible transfer of infectious diseases. The present study investigated the cognition-enhancing properties of different types of PS in rats. Seventeen-month-old male Fischer 344 rats were treated daily with a dose of 15 mg/kg of PS derived from bovine cortex (BC-PS), soybean (S-PS), egg (E-PS), or vehicle (n = 9 for each group). The effects of treatment were evaluated in three different behavioral tests. An open field test was conducted to examine the effects of treatment on psychomotor behavior. Two other tests (Morris water escape task and two-way active avoidance) assessed treatment effects on the cognitive performance of rats. Treatment with the different forms of PS did not affect the psychomotor or spatial discrimination performance of the rats. In accordance with previous studies, the cognition-enhancing effects of BC-PS were observed in the two-way active avoidance task. It appeared that the cognition-enhancing effects of S-PS were not different from those of BC-PS. The performance of rats treated with E-PS did not deviate from that of vehicle-treated rats. On the basis of the present study, it was concluded that S-PS, but not E-PS, may have comparable effects on cognition when compared with BC-PS.

Local inhibition of hippocampal nitric oxide synthase does not impair place learning in the Morris water escape task in rats.

Recent studies have provided evidence that nitric oxide (NO) has a role in certain forms of memory formation. Spatial learning is one of the cognitive abilities that has been found to be impaired after systemic administration of an NO-synthase inhibitor. As the hippocampus has a pivotal role in spatial orientation, the present study examined the role of hippocampal NO in spatial learning and reversal learning in a Morris task in adult rats. It was found that N omega-nitro-L-arginine infusions into the dorsal hippocampus affected the manner in which the rats were searching the submerged platform during training, but did not affect the efficiency to find the spatial location of the escape platform. Hippocampal NO-synthase inhibition did not affect the learning of a new platform position in the same water tank (i.e. reversal learning). Moreover, no treatment effects were observed in the probe trials (i.e. after acquisition and after reversal learning), indicating that the rats treated with N omega-nitro-L-arginine had learned the spatial location of the platform. These findings were obtained under conditions where the NO synthesis in the dorsal hippocampus was completely inhibited. On the basis of the present data it was concluded that hippocampal NO is not critically involved in place learning in rats.

Intra-striatal haloperidol and scopolamine injections: effects on choice reaction time performance in rats.

In this study the behavioral consequences of intra-striatal haloperidol and scopolamine injections were examined using a reaction time task. Haloperidol was found to increase the response time of the rats and had a modest effect on the motor components of the task. The manner in which haloperidol affected the response time distribution suggested that this drug affected attentional functions. Scopolamine did not affect the reaction time or motor performance in the reaction time task. However, a clear decrease in the number of completed trials and an increase in anticipatory responses was observed. At present no ready explanation could be given for the behavioral effects of scopolamine. The present data suggest that although dopamine and acetylcholine are intimately related in the striatal network and have been supposed to have antagonistic functions, the behavioral consequences of blockade of dopamine and acetylcholine receptors are dissimilar.

Effects of haloperidol and d-amphetamine on working and reference memory performance in a spatial cone field task.

The present study was designed to examine the effects of haloperidol (0.03, 0.1 mg/kg, intraperitoneal (i.p.)) and d-amphetamine (0.3, 1.0 mg/kg, i.p.) in a cone field task in which spatial working and reference memory (WM and RM, respectively) were assessed simultaneously. The apparatus is a large open field in which 16 cones are placed with four cones baited by placing a food reward in the top. After food-deprived rats had acquired this task they showed a high level of performance, that is avoided visits to non-baited cones (RM) and made few revisits to baited cones (WM). Haloperidol had a greater negative effect on RM than on WM performance, but also decreased the number of food rewards collected. On the other hand, the high dose of d-amphetamine induced a clear WM performance deficit, whereas RM performance was only marginally affected. The present study suggests that spatial discrimination performance can be dissociated using the measures RM and WM in the present task. Further, the deficits induced by haloperidol and d-amphetamine may not be specifically related with impaired mnemonic functions.

Acute effects of acetyl-L-carnitine on sodium cyanide-induced behavioral and biochemical deficits.

In the present study we investigated the effects of acute treatment with acetyl-L-carnitine (50 mg/kg, i.v. 90 min before the sodium cyanide injection) on a sodium cyanide-induced behavioral deficit in the Morris water escape task. In a first experiment the spatial discrimination performance of the rats was found to be dose-dependently impaired after an i.c.v. injection of sodium cyanide (2.5 and 5.0 microg). Acute treatment with acetyl-L-carnitine was found to increase the behavioral deficit after sodium cyanide. These findings were replicated in a second experiment. Based on these results it can be argued that an acute administration of acetyl-L-carnitine appears to potentiate a sodium cyanide-induced behavioral deficit. An additional in vitro experiment with rat brain synaptosomes showed clear effects of administered sodium cyanide on the energy-dependent incorporation of inositol into phosphoinositides and on the ATP concentration. In vitro acetyl-L-carnitine administration had no effect on the sodium cyanide-induced energy depletion. The negative behavioral findings are in contrast with our previously found protective effect of chronic treatment with acetyl-L-carnitine (via drinking water) on the sodium cyanide-induced behavioral deficit. Since chronic acetyl-L-carnitine treatment has no effect on the phosphoinositide metabolism it was suggested that acetyl-L-carnitine may act via the formation of an ATP-independent reservoir of activated acyl groups. Thus, fatty acids as acylated derivatives can be used for reacylation processes during an acute period of energy depletion. However, we have no clear explanation for the discrepancy in behavioral results between the chronic vs acute treatment of acetyl-L-carnitine at present. Further research is needed to characterize the mechanism of action of acetyl-L-carnitine in relation to sodium cyanide.

State-dependent impairment in object recognition after hippocampal NOS inhibition.

In the present study we investigated the consequences of hippocampal nitric oxide synthase (NOS) inhibition on the performance in an object recognition task in rats. In a first study we injected Nomega-nitro-L-arginine (L-NA) into the hippocampus directly after the first trial. One hour later the discrimination performance of the animals was assessed. It was found that 10 microg and 30 microg, but not 3 microg, L-NA impaired the performance of the rats. In a second study in which we injected L-NA 45 min before the first trial no effects of treatment (10 microg and 30 microg) were observed. Since treatment with 30 microg has been found to inhibit hippocampal NOS almost completely and lasts longer than 2 h, it was concluded that hippocampal NOS inhibition induced a state-dependent performance deficit. Consequently, studies that examine the effects of NOS inhibition on cognitive functions should take this confounding effect into account.

Discrimination of relative numerosity and stimulus mixture by pigeons with comparable tasks.

Arrays of small squares of 2 colors were presented in various proportions to pigeons on a video screen. Birds pecked differentially at the left or right side of the screen to obtain grain. In Experiment 1, pecking at 1 side was correct when more blue than red elements were Proportions of responses to the 2 locations reflected the proportions of elements in an orderly manner and were little affected by alterations in spacing or size of elements. When red Experiment 2, 1 side of the screen was correct when uniform red or blue arrays were presented; the other was correct for mixed arrays. Orderly gradients of response location reflected degree of stimulus mixture. Good transfer was obtained with green and blue elements. These results support the robust nature of discriminations of emergent properties of complex arrays when stimuli are equally associated with reinforcement and when response location, and not response rate, indicates stimulus control.

Spatial discrimination learning and choline acetyltransferase activity in streptozotocin-treated rats: effects of chronic treatment with acetyl-L-carnitine.

Treatment of rats with i.c.v. injected streptozotocin (STREP) may provide a relevant model of neurodegeneration that is induced by a decrease in the central metabolism of glucose. Acetyl-L-carnitine (ALCAR) enhances the utilization of alternative energy sources and by such a mechanism of action ALCAR could antagonize the effects of STREP treatment. In this study the effects of chronic treatment with ALCAR were evaluated on spatial discrimination learning in the Morris task and choline acetyltransferase (ChAT) activity of middle-aged STREP-treated rats. Chronic treatment with ALCAR attenuated both the STREP-induced impairment in spatial bias and the decrease in hippocampal ChAT activity. These findings indicate that ALCAR treatment has a neuroprotective effect, although further studies are needed to characterize the mechanism of action of ALCAR in this model.