Wiel Honig

Pulsed and continous radiofrequency current adjacent to the cervical dorsal root ganglion of the rat induces late cellular activity in the dorsal horn

Background: Pulsed radiofrequency treatment has recently been described as a non-neurodestructive or minimally neurodestructive alternative to radiofrequency heat lesions. In clinical practice long-lasting results of pulsed radiofrequency treatment adjacent to the cervical dorsal root ganglion for the management of chronic radicular spinal pain have been reported without neurologic complications. However, the mode of action is unclear. An early (3 h) effect of pulsed radiofrequency as measured by an increase of c-Fos in the pain-processing neurons of the dorsal horn of rats has been described in the literature. This effect was not mediated by tissue heating. The authors investigated a possible late or long-term effect of three different radiofrequency modalities. Methods: Cervical laminectomy was performed in 19 male Wistar rats. The cervical dorsal root ganglion was randomly exposed to one of the four interventions: sham, continuous radiofrequency current at 67 centigrades, or pulsed radiofrequency current for 120 s or 8 min. The animals were sacrificed and the spinal cord was prepared for c-Fos labeling 7 days after the intervention. Results: The number of c-Fos immunoreactive cells in the dorsal horn was significantly increased in the three different radiofrequency modalities as compared with sham. No significant difference was demonstrated between the three active intervention groups. Conclusions: The authors demonstrated a late neuronal activity in the dorsal horn after exposure of the cervical dorsal root ganglion to different radiofrequency modalities, which was not temperature dependent.

cGMP, but not cAMP, in rat hippocampus is involved in early stages of object memory consolidation.

The present study investigates the role of cGMP and cAMP on the memory performance in the object recognition task in rats. The analogue 8-Br-GMP or 8-Br-cAMP was administered bilaterally into the hippocampus (0, 1, 3 and 10 microg in 0.5 microl saline/site) immediately after the exposure to two identical objects. After 24 h, saline-treated animals spent equal times exploring a new and the familiar object demonstrating that they did not recognize the familiar one. However, a dose-dependent improvement in object recognition was found after injection of 8-Br-cGMP. In contrast, 8-Br-cAMP did not improve the memory performance at the doses tested. These results indicate that hippocampal cGMP but not cAMP is involved in early stages of consolidation of object memory.

Apolipoprotein E Protects against Neuropathology Induced by a High-Fat Diet and Maintains the Integrity of the Blood-Brain Barrier during Aging

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.

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.

Effects of intra-hippocampal scopolamine injections in a repeated spatial acquisition task in the rat

The involvement of hippocampal cholinergic synapses in spatial discrimination learning was evaluated by locally administering scopolamine into the hippocampus. Sixteen 16-month-old male Lewis rats received bilaterally implanted cannulae aimed at the dorsal part of the hippocampus. The rats were trained on a repeated acquisition test in the Morris water-escape task. In this procedure the invisible platform is randomly moved from day to day to one of four possible locations. Thus, the rat has to learn to localize the platform from day to day. On each day the rats received four pairs of trials. Scopolamine injections (35 µg in 1 μl per hippocampus) were given to one group (n=8) on days 5 and 7. On days 6 and 8 all rats received saline injections. Place learning was retarded in the scopolamine-treated rats during the first swims of pairs of trials. During second swims the scopolamine-treated rats showed a general performance deficit, indicating that first and second swims were differentially affected. The data support the hypothesis that cholinergic neurotransmission in the dorsal hippocampus is involved in spatial learning processes.

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 Nω‐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 Nω‐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.

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 Nω-nitro-L-arginine (LNA) into the hippocampus directly after the first trial. One hour later the discrimination performance of the animals was assessed. It was found that 1 μ g and 3 O°g, but not 3 μg, 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 μg and 3 Oμg) were observed. Since treatment with 30 μg 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.

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.

Neurite outgrowth promoting effects of enriched and mixed OEC/ONF cultures.

Olfactory ensheathing cell (OEC) transplants stimulate axon regeneration and partial functional recovery after spinal cord injury. However, it remains unclear whether enriched OEC or mixed transplants of OEC and olfactory nerve fibroblasts (ONF) are optimal for stimulating axon regrowth. The neurite outgrowth stimulating effects of enriched OEC, ONF, and mixed OEC/ONF cultures on neonatal cerebral cortical neurons were compared using co-cultures. We show that (1) OEC are more neurite outgrowth promoting than ONF, and (2) ONF do not enhance the neurite outgrowth stimulating effects of OEC in mixed OEC/ONF cultures. Hence, our data indicate that there is no preference for the use of enriched OEC or mixed OEC/ONF cultures with respect to stimulation of neurite growth in vitro.

Mice lacking L1 have reduced CGRP fibre in-growth into spinal transection lesions

Repair strategies for spinal cord injury often focus on promoting regeneration of injured axons and stimulating subsequent functional recovery. Although many of these strategies have proven their merits, less is known about potential unwanted side-effects, such as sprouting of nociceptive CGRP immunoreactive axons, which may bring about pain-related behavior. Sprouting of CGRP axons into lesion sites spontaneously occurs after spinal cord injury (SCI). Using L1-deficient mice we show a reduction of such CGRP growth response. This reduction was specific for CGRP axons since the overall neurofilament positive fibre in-growth into the spinal lesion site was not affected. Our results may have important implications on the development and assessment of repair strategies that should not only stimulate functional recovery, but also prevent the development of pain or autonomic dysreflexia.