Forever young: how to control the elongation, differentiation, and proliferation of cells using nanotechnology.

Within the emerging field of stem cells there is a need for an environment that can regulate cell activity, to slow down differentiation or proliferation, in vitro or in vivo while remaining invisible to the immune system. By creating a nanoenvironment surrounding PC12 cells, Schwann cells, and neural precursor cells (NPCs), we were able to control the proliferation, elongation, differentiation, and maturation in vitro. We extended the method, using self-assembling nanofiber scaffold (SAPNS), to living animals with implants in the brain and spinal cord. Here we show that when cells are placed in a defined system we can delay their proliferation, differentiation, and maturation depending on the density of the cell population, density of the matrix, and the local environment. A combination of SAPNS and young cells can be implanted into the central nervous system (CNS), eliminating the need for immunosuppressants.

Using nanotechnology to design potential therapies for CNS regeneration.

The nanodelivery of therapeutics into the brain will require a step-change in thinking; overcoming the blood brain barrier is one of the major challenges to any neural therapy. The promise of nanotechnology is that the selective delivery of therapeutics can be delivered through to the brain without causing secondary damage. There are several formidable barriers that must be overcome in order to achieve axonal regeneration after injury in the CNS. The development of new biological materials, in particular biologically compatible scaffolds that can serve as permissive substrates for cell growth, differentiation and biological function is a key area for advancing medical technology. This review focuses on four areas: First, the barriers of delivering therapies to the central nervous system and how nanotechnology can potentially solve them; second, current research in neuro nanomedicine featuring brain repair, brain imaging, nanomachines, protein misfolding diseases, nanosurgery, implanted devices and nanotechnologies for crossing the blood brain barrier; third, health and safety issues and fourth, the future of neuro nanomedicine as it relates to the pharmaceutical industry.

Differential interaction of platelet-activating factor and NMDA receptor function in hippocampal and dorsal striatal memory processes.

The interaction between platelet activating factor (PAF) and NMDA receptor function in hippocampal and dorsal striatal memory processes was examined. In both a hidden and a visible platform water maze task, peripheral post-training injection of MK-801 (0.05 mg/kg) impaired memory. Post-training intrahippocampal infusions of PAF (1.0 microg/0.5 microl) enhanced memory in the hidden platform task, while intradorsal striatal infusion of PAF (1.0 microg/0.5 microl) enhanced memory in the visible platform task. The memory impairing effects of post-training injection of MK-801 was blocked by concurrent intrahippocampal infusion of PAF. In contrast, post-training injection of MK-801 blocked the memory enhancing effects of concurrent intradorsal striatal infusion of PAF. The results suggest that (1) the memory enhancing effects of intracerebral PAF infusion involve an interaction with NMDA receptor function, and (2) the nature of this interaction may represent a differential mechanism mediating the distinct roles of the hippocampus and dorsal striatum in cognitive memory and stimulus-response habit formation, respectively.

Effects of posttraining intrahippocampal injections of platelet-activating factor and PAF antagonists on memory.

The present experiments examined the effects of posttraining intrahippocampal injections of the degradative enzyme-resistant methylcarbamyl analog of the bioactive phospholipid platelet-activating factor (mc-PAF) and the platelet-activating factor (PAF) receptor antagonists BN52021 and BN 50730 on memory in male Long-Evans rats trained in a hidden platform version of the Morris water maze. Following an eight-trial training session, rats received a unilateral intrahippocampal injection of mc-PAF (0.5, 1.0, or 2.0 microgram/0.5 microliter), lyso-PAF (1.0 microgram/0.5 microliter), the cell surface PAF receptor antagonist BN 52021 (0.25, 0.5, or 1.0 micrigram/0.5 microliter/, the intracellular PAF receptor antagonist BN 50730 (2.0, 5.0, or 10.0 microgram/0.5 microliter), or vehicle (50% DMSO in 0.9% saline; 0.5 microliter). On a retention test conducted 24 h after training, the escape latencies of rats administered mc-PAF (1.0 or 2.0 microgram) were significantly lower than those of the vehicle-injected controls, demonstrating a memory-enhancing effect of mc-PAF. Injections of lyso-PAF, a structurally similar metabolite of PAF, had no influence on memory, indicating that the memory-enhancing effect of mc-PAF is not caused by membrane perturbation by the phospholipid. The retention test escape latencies of rats administered BN 52021 (0.5 microgram) and BN 50730 (5.0 or 10 microgram) were significantly higher than those of the controls, indicating a memory impairing effect of both PAF antagonists. When mc-PAF, BN 52021, or BN 50730 was administered 2 h posttraining, no effect on retention was observed, indicating a time-dependent effect of the neuroactive substances on memory storage. The findings suggest a role for endogenous PAF in hippocampal-dependent memory processes.

Amygdala modulation of multiple memory systems: hippocampus and caudate-putamen.

A series of five experiments examined the differential mnemonic roles of the hippocampus and caudate-putamen and the modulatory influence of the amygdala on hippocampal and caudate-putamen memory processes. Findings indicate that (a) posttraining intrahippocampal injections of amphetamine selectively enhance memory in a hidden platform water maze task, (b) posttraining intracaudate injections of amphetamine selectively enhance memory in a visible platform water maze task, (c) posttraining intra-amygdala injections of amphetamine enhance memory in both water maze tasks, (d) preretention intrahippocampal lidocaine injections block expression of the memory enhancing effects of posttraining intrahippocampal amphetamine injections in the hidden platform task, (e) preretention intracaudate lidocaine injections block expression of the memory enhancing effects of posttraining intracaudate amphetamine injections in the visible platform task, (f) preretention intra-amygdala lidocaine injections do not block the memory enhancing effect of posttraining intra-amygdala amphetamine injections on either task, (g) in the hidden platform task, posttraining intrahippocampal, but not intracaudate, lidocaine injections block the memory enhancing effects of posttraining intra-amygdala amphetamine, (h) in the visible platform task, posttraining intracaudate, but not intrahippocampal, lidocaine injections block the memory enhancing effects of posttraining intra-amygdala amphetamine. The findings indicate a double dissociation between the roles of the hippocampus and caudate-putamen in memory and suggest that the amygdala exerts a modulatory influence on both the hippocampal and caudate-putamen memory systems.

Posttraining estradiol injections enhance memory in ovariectomized rats: cholinergic blockade and synergism.

The present experiments examined acute posttraining estrogenic influences on memory in ovariectomized rats. In experiment 1 rats received a single 8-trial (30-s ITI) training session with a submerged escape platform located in the same quadrant of a circular water maze on all trials. Following trial 8, rats received a posttraining intraperitoneal injection of either an estradiol-cyclodextrin inclusion complex (0.1, 0.2, or 0.4 mg/kg) or saline. On a retention test session 24 h later, the escape latencies of rats given injections of estradiol (0.2 mg/kg) were significantly lower than those of saline-treated rats, indicating an enhancement of memory. Injections of estradiol delayed 2 h posttraining did not affect retention, demonstrating a time-dependent effect of estradiol on memory storage processes. In experiment 2a, posttraining injections of the cholinergic muscarinic receptor antagonist scopolamine (0.4 mg/kg) impaired memory in ovariectomized rats. In experiment 2b, the memory-enhancing effect of estradiol (0.2 mg/kg) was blocked by concurrent posttraining administration of a subeffective dose (0.1 mg/kg) of scopolamine, suggesting an interaction between estradiol and muscarinic cholinergic systems in memory modulation. In experiment 3a, posttraining injections of the cholinergic muscarinic receptor agonist oxotremorine (0.2 mg/kg) enhanced memory in ovariectomized rats. In experiment 3b, concurrent posttraining injection a subeffective dose of estradiol (0.1 mg/kg) and a subeffective dose of oxotremorine (0.1 mg/kg) enhanced memory, indicating a synergistic effect of estradiol and muscarinic receptor activation on memory.

Intra-hippocampal estradiol infusion enhances memory in ovariectomized rats.

Ovariectomized adult Long-Evans rats received an eight-trial training session in a hippocampal-dependent hidden platform water maze task. Following trial 8, rats received an intra-hippocampal injection of estradiol in a water soluble cyclodextrin inclusion complex (1.0, 2.0 or 5.0 micrograms/0.5 microliter), or saline. Twenty-four hours later, the retention test escape latencies of rats administered post-training intra-hippocampal injections of estradiol (5.0 micrograms) were significantly lower than those of saline treated rats, indicating a memory-enhancing effect of estradiol. Injections of estradiol (5.0 micrograms) given 2 h post-training had no effect on retention, indicating a time-dependent effect of estradiol on memory storage processes.

Posttraining injections of MK-801 produce a time-dependent impairment of memory in two water maze tasks.

The role of glutamatergic N-methyl-D-aspartate (NMDA) receptors in memory storage processes was examined using systemic posttraining injections of MK-801. Male Long-Evans rats received an eight-trial (30-s ITI) training session on a spatial or cued water maze task. In the spatial task, a submerged escape platform was located in the same quadrant of the maze on all trials. In the cued task, a visible escape platform was located in a different quadrant of the maze on each trial. Following Trial 8 in both tasks, the rats received a posttraining intraperitoneal injection of the NMDA receptor antagonist MK-801 (0.025, 0.05, 0.1, or 0.2 mg/kg) or saline. On a retention test session 24 h later, latency to mount the escape platform was used as a measure of memory. In both tasks, the retention test escape latencies of animals given MK-801 (0.05 and 0.1 mg/kg) were significantly higher than those of saline-injected controls, indicating a drug-induced impairment of memory. Injections of MK-801 (0.05 mg/kg) did not affect retention when administered 2 h posttraining in either task, indicating that the effects of MK-801 on retention are not due to an influence on non-mnemonic factors. Control experiments indicated that the memory impairing effects of MK-801 were due to an influence on memory for the type of discrimination training given (i.e., spatial or cued) and not due to an influence on a mnemonic strategy common to both tasks. The findings indicate a time-dependent role for NMDA receptor function in memory storage processes.

Double dissociation of hippocampal and dorsal-striatal memory systems by posttraining intracerebral injections of 2-amino-5-phosphonopentanoic acid.

Rats received an 8-trial training session on a spatial or cued task in a water maze, followed by a posttraining intracerebral injection of AP5 or saline. On a retention test 24 hr later, latency to mount the escape platform was used as a measure of memory. Intrahippocampal (10 micrograms), but not intra-dorsal striatal (2, 5, or 10 micrograms), injection of AP5 impaired memory in the spatial task. In contrast, intra-dorsal striatal (2 micrograms), but not intrahippocampal (2, 5, or 10 micrograms) injection of AP5 impaired memory in the cued task. Intracerebral injections of AP5 delayed 2 hr posttraining were ineffective. The findings indicate a double dissociation of the roles of the hippocampus and dorsal striatum in memory, a role for N-methyl-D-aspartate receptor function in posttraining memory processes, and a glutamatergic modulation of both hippocampal and dorsal striatal memory processes, suggesting that different forms of memory may share a similar neurochemical basis.

Effects of intrastriatal injections of platelet-activating factor and the PAF antagonist BN 52021 on memory.

The present experiments examined the effects of posttraining intra-dorsal striatal (i.e., caudate-putamen) injections of the phospholipid methylcarbamyl platelet-activating factor (mc-PAF) and the platelet-activating factor (PAF) antagonist BN 52021 on memory using a striatal-dependent cued water maze task. Male Long-Evans rats received an eight-trial training session in which a visibly cued escape platform was located in a different quadrant of the maze on each trial, followed by an intrastriatal injection of mc-PAF (0.5, 1.0, or 2.0 micrograms/0.5 microliter), BN 52021 (0.25, 0.5, or 1.0 microgram/0.5 microliter), or vehicle (DMSO; 0.5 microliter). On a retention test 24 h later, the escape latencies of rats given mc-PAF (1.0, 2.0 micrograms) wee significantly lower than those of vehicle-injected controls, indicating a memory enhancing effect of mc-PAF. The retention test escape latencies of rats given BN 52021 (0.5, 1.0 microgram) were significantly higher than those of vehicle-injected controls, indicating a memory impairing effect of BN 52021. Injections of mc-PAF or BN 52021 did not affect retention when administered 2-h posttraining, indicating a time-dependent effect of the drugs on memory storage. The findings indicate a role for endogenous PAF function in striatal-dependent memory processes.