Gemfibrozil, food and drug administration-approved lipid-lowering drug, increases longevity in mouse model of late infantile neuronal ceroid lipofuscinosis.

Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL) is a rare neurodegenerative disease caused by mutations in the Cln2 gene that leads to deficiency or loss of function of the tripeptidyl peptidase 1 (TPP1) enzyme. TPP1 deficiency is known to cause the accumulation of autofluoroscent lipid-protein pigments in brain. Similar to other neurodegenerative disorders, LINCL is also associated with neuroinflammation and neuronal damage. Despite investigations, no effective therapy is currently available for LINCL. Therefore, we administered gemfibrozil (gem), an food and drug administration (FDA)-approved lipid-lowering drug, which has been shown to stimulate lysosomal biogenesis and induce anti-inflammation, orally, at a dose of 7.5 mg/kg body wt/day to Cln2(-/-) mice. We observed that gem-fed Cln2(-/-) mice lived longer by more than 10 weeks and had better motor activity compared to vehicle (0.1% Methyl cellulose) treatment. Gem treatment lowered the burden of storage materials, increased anti-inflammatory factors like SOCS3 and IL-1Ra, up-regulated anti-apoptotic molecule like phospho-Bad, and reduced neuronal apoptosis in the brain of Cln2(-/-) mice. Collectively, this study reinforces a neuroprotective role of gem that may be of therapeutic interest in improving the quality of life in LINCL patients.

Locomotor recovery after spinal cord hemisection/contusion injures in bonnet monkeys: footprint testing--a minireview.

Spinal cord injuries usually produce loss or impairment of sensory, motor and reflex function below the level of damage. In the absence of functional regeneration or manipulations that promote regeneration, spontaneous improvements in motor functions occur due to the activation of multiple compensatory mechanisms in animals and humans following the partial spinal cord injury. Many studies were performed on quantitative evaluation of locomotor recovery after induced spinal cord injury in animals using behavioral tests and scoring techniques. Although few studies on rodents have led to clinical trials, it would appear imperative to use nonhuman primates such as macaque monkeys in order to relate the research outcomes to recovery of functions in humans. In this review, we will discuss some of our research evidences concerning the degree of spontaneous recovery in bipedal locomotor functions of bonnet monkeys that underwent spinal cord hemisection/contusion lesions. To our knowledge, this is the first report to discuss on the extent of spontaneous recovery in bipedal locomotion of macaque monkeys through the application of footprint analyzing technique. In addition, the results obtained were compared with the published data on recovery of quadrupedal locomotion of spinally injured rodents. We propose that the mechanisms underlying spontaneous recovery of functions in spinal cord lesioned monkeys may be correlated to the mature function of spinal pattern generator for locomotion under the impact of residual descending and afferent connections. Moreover, based on analysis of motor functions observed in locomotion in these subjected monkeys, we understand that spinal automatism and development of responses by afferent stimuli from outside the cord could possibly contribute to recovery of paralyzed hindlimbs. This report also emphasizes the functional contribution of progressive strengthening of undamaged nerve fibers through a collateral sprouts/synaptic plasticity formed in partially lesioned cord of monkeys.

Locomotor Behavior Analysis in Spinal Cord Injured Macaca radiata after Predegenerated Peripheral Nerve Grafting-A Preliminary Evidence.

INTRODUCTION: Primate animal models are being utilized to explore novel therapies for spinal cord injuries. This study aimed to evaluate the efficiency of the transplantation of predegenerated nerve segments in unilateral spinal cord-hemisected bonnet monkeys' (Macaca radiata) locomotor functions using the complex runways. MATERIALS AND METHODS: The bonnet monkeys were initially trained to walk in a bipedal motion on grid and staircase runways. In one group of trained monkeys, surgical hemisection was made in the spinal cord at the T12-L1 level. In the other group, hemisection was induced in the spinal cord, and the ulnar nerve was also transected at the same time (transplant group). After one week, the hemisected cavity was reopened and implanted with predegenerated ulnar nerve segments obtained from the same animal of the transplant group. RESULTS: All the operated monkeys showed significant deficits in locomotion on runways at the early postoperative period. The walking ability of operated monkeys was found to be gradually improved, and they recovered nearer to preoperative level at the fourth postoperative month, and there were no marked differences. CONCLUSION: The results demonstrate that there were no significant improvements in the locomotion of monkeys on runways after the delayed grafting of nerve segments until one year later. The failure of the predegenerated nerve graft as a possible therapeutic strategy to improve the locomotion of monkeys may be due to a number of factors set in motion by trauma, which could possibly prevent the qualities of regeneration. The exact reason for this ineffectiveness of predegenerated nerve segments and their underlying mechanism is not known.

BPOZ-2 Gene Delivery Ameliorates Alpha-Synucleinopathy in A53T Transgenic Mouse Model of Parkinson's Disease.

Ankyrin-rich BTB/POZ domain containing protein-2 or BPOZ-2, a scaffold protein, has been recently shown to control the degradation of many biological proteins ranging from embryonic development to tumor progression. However, its role in the process of neuronal diseases has not been properly explored. Since, abnormal clearance of metabolic proteins contributes to the development of alpha-synuclein (α-syn) pathologies in Parkinson's disease (PD), we are interested to explore if BPOZ-2 participates in the amelioration of α-syn in vivo in basal ganglia. Here we report that lentiviral administration of bpoz-2 gene indeed lowers the burden of α-syn in DA neurons in the nigra of A53T transgenic (A53T-Tg) mouse. Our detailed immunological analyses have shown that the overexpression of bpoz-2 dramatically improves both somatic and neuritic α-syn pathologies in the nigral DA neurons. Similarly, the specific ablation of bpoz-2 by lentiviral-shRNA stimulates the load of monomeric and polymeric forms of α-syn in the nigral DA neurons of A53T-Tg. While investigating the mechanism, we observed that BPOZ-2 was involved in a protein-protein association with PINK1 and therefore could stimulate PINK1-dependent autophagic clearance of α-syn. Our results have demonstrated that bpoz-2 gene delivery could have prospect in the amelioration of alpha-synucleinopathy in PD and other Lewy body diseases.

Neurotrophic factor therapy for Parkinson's disease.

Parkinson's disease (PD) is a chronic, progressive neurodegenerative movement disorder for which there is currently no effective therapy. Over the past several decades, there has been a considerable interest in neuroprotective therapies using trophic factors to alleviate the symptoms of PD. Neurotrophic factors (NTFs) are a class of molecules that influence a number of neuronal functions, including cell survival and axonal growth. Experimental studies in animal models suggest that members of neurotrophin family and GDNF family of ligands (GFLs) have the potent ability to protect degenerating dopamine neurons as well as promote regeneration of the nigrostriatal dopamine system. In clinical trials, although no serious adverse events related to the NTF therapy has been reported in patients, they remain inconclusive. In this chapter, we attempt to give a brief overview on several different growth factors that have been explored for use in animal models of PD and those already used in PD patients.