Autologous skin-derived neural precursor cell therapy reverses canine Alzheimer dementia-like syndrome in a proof of concept veterinary trial.

BACKGROUND: Older companion dogs naturally develop a dementia-like syndrome with biological, clinical and therapeutic similarities to Alzheimer disease (AD). Given there has been no new safe, clinically effective and widely accessible treatment for AD for almost 20 years, an all-new cell therapeutic approach was trialled in canine veterinary patients, and further modelled in aged rats for more detailed neurobiological analysis. METHODS: A Phase 1/2A veterinary trial was conducted in N = 6 older companion dogs with definitive diagnosis of Canine Cognitive Dysfunction (CCD). Treatment comprised direct microinjection of 250,000 autologous skin-derived neuroprecursors (SKNs) into the bilateral hippocampus using MRI-guided stereotaxis. Safety was assessed clinically and efficacy using the validated Canine Cognitive Dysfunction Rating Scale (CCDR) at baseline and 3-month post treatment. Intention to treat analysis imputed a single patient that had a surgical adverse event requiring euthanasia. Three dog brains were donated following natural death and histology carried out to quantify Alzheimer pathology as well as immature neurons and synapses; these were compared to a brain bank (N = 12) of untreated aged dogs with and without CCD. Further, an age-related memory dysfunction rat model (N = 16) was used to more closely evaluate intrahippocampal engraftment of canine SKN cells, focusing on mnemonic and synaptic effects as well as donor cell survival, neurodifferentation and electrophysiologic circuit integration in a live hippocampal slice preparation. RESULTS: Four out-of-five dogs improved on the primary clinical CCDR endpoint, three fell below diagnostic threshold, and remarkably, two underwent full syndromal reversal lasting up to 2 years. At post mortem, synaptic density in the hippocampus specifically was nine standard deviations above non-treated dogs, and intensity of new neurons also several fold higher. There was no impact on AD pathology or long-term safety signals. Modelling in aged rats replicated the main canine trial findings: hippocampally-dependent place memory deficits were reversed and synaptic depletion rescued. In addition, this model confirmed donor cell survival and migration throughout the hippocampus, neuronal differentiation in situ, and physiologically-correct integration into pyramidal layer circuits. CONCLUSIONS: With further development, SKN cell therapy may have potential for treating carefully chosen AD patients based on neurosynaptic restoration in the hippocampus.

Effect of prolonged treatment with haloperidol on "emotional" defecation and movement in rats in a well-habituated environment.

Sixteen adult male Wistar rats were administered either haloperidol (n = 8), 0.5 mg/kg, or saline (placebo) (n = 8) by subcutaneous injection three times per week for 6 weeks, and were again injected after a 6-week drug-free period. The study was conducted in a well-habituated, distinctive environment to which the rats were introduced 1 hour before the injection on each occasion. The fecal bolus counts 1 hour before and 2 hours after drug injection were obtained, as well as movement counts repeatedly in epochs of 90 seconds upon introduction to the cages and after the injections. Haloperidol produced an overall increase in defecation in the 2 hours after drug injection compared with placebo. The post-drug bolus counts for haloperidol-treated rats were lower in week 2 compared with week 1, but the difference from placebo for this reduction was not significant, and it did not persist beyond week 4. The haloperidol-treated group showed a significant increase in the predrug bolus counts from week 5, suggesting a conditioned response to the cage environment. The haloperidol-treated rats were markedly less mobile than the placebo-treated rats, and with repeated exposure to haloperidol, they tended to develop hypomotility earlier. No tolerance to the movement effect was observed. The defecation and movement effects of haloperidol at 12 weeks were no different from those at week 1. This study supports earlier work indicating that haloperidol produces a dysphoric effect in rats, and it suggests that this effect does not habituate over 6 weeks of repeated administration. It does not replicate the motor aspect of akathisia seen in humans.

Neuroleptic-induced defecation in rats as a model for neuroleptic dysphoria.

Two groups of 32 rats were challenged in a well-habituated environment with haloperidol (0.5 mg/kg), haloperidol (0.1 mg/kg), domperidone (0.1 mg/kg), or saline to study the effect of these drugs on defecation--an index of emotionality--and voluntary movements in the 2 hours after the injection. The haloperidol-treated rats in the high-dose condition had significantly more bolus counts in the 2 hours after the injection than were observed in the groups treated with domperidone (a peripheral dopamine D2 receptor antagonist) or placebo. All movements were greatly reduced in the haloperidol-treated rats and, in this group, the ones with more bolus counts did not differ in their activity levels from those with fewer bolus counts. There was a trend for the rats that were less mobile at 10 minutes after the injection to produce more boli in the 2-hour period. Our study, therefore, replicates the findings of Sanberg (1980) and Russell et al. (1987a, 1987b) that haloperidol increases "emotional" defecation in rats in well-habituated environments, but the same model does not replicate the motor component of neuroleptic-induced akathisia seen in human subjects.