The multifunctional neuropeptide Cocaine and Amphetamine Regulated Transcript (CART) is secreted from hypothalamus, pituitary, adrenal gland and pancreas. It also can be found in circulatory system. This feature suggests a general role for CART in different cells. In the present study, we demonstrate that CART protects mitochondrial DNA (mtDNA), cellular proteins and lipids against the oxidative action of hydrogen peroxide, a widely used oxidant. Using cis-parinaric acid as a sensitive reporting probe for peroxidation in membranes, and a lipid-soluble azo initiator of peroxyl radicals, 2,2′-Azobis(2,4-dimethylvaleronitrile) we found that CART is an antioxidant. Furthermore, we found that CART localized to mitochondria in cultured cells and mouse brain neuronal cells. More importantly, pretreatment with CART by systemic injection protects against a mouse oxidative stress model, which mimics the main features of Parkinson's disease. Given the unique molecular structure and biological features of CART, we conclude that CART is an antioxidant peptide (or antioxidant hormone). We further propose that it may have strong therapeutic properties for human diseases in which oxidative stress is strongly involved such as Parkinson's disease.

IntroductionIn two clinical trials the mouse antiidiotypic monoclonal antibody (MAb) MF1 1-30, which bears the internal image of human high-molecular-weight-melanoma-associated antigen (HMW-MAA) was administered by subcutaneous route without adjuvants to patients with stage IV malignant melanoma on day 0, 7, and 28. The development of monoclonal antibodies to human tumorassociated antigens (TAA)' that meet the criteria to be used as targets for immunotherapy (for review, see 1-3) has rekindled interest in the application of immunotherapeutic approaches to malignant diseases. Among them, the use of antiidiotypic antibodies, i.e., antibodies to determinants expressed on the variable region of anti-TAA antibodies, is attracting much attention, since in animal model systems the immune response induced by this type of active specific immunotherapy is associated with an improvement of the course of the disease (4-6). The rationale underlying this approach is represented by the ability ofantiidiotypic antibodies that bear the mirror image of TAA to elicit and/or enhance anti-TAA immune responses; such responses may eventually result in the destruction of tumor cells.In order to test the usefulness of mouse antiidiotypic MAb elicited with syngeneic anti-TAA MAb to implement active specific immunotherapy, we have selected malignant melanoma as our model system for a number of reasons (7). First, a therapeutic approach based on manipulation of the patient's immune response has a potential for success in this disease because ofthe likely role of immunological factors in its pathogenesis and in its clinical course (8). Second, testing of a novel therapeutic approach finds justification in the lack of progress and limited success of available therapeutic modalities in malignant melanoma (9). Third, utilizing mouse MAb, we have identified a membrane-bound melanoma-associated antigen, referred to as HMW-MAA (high-molecular-weight-melanoma-associated antigen). This antigen represents a useful target for active and passive immunotherapy because of its high frequency in melanoma lesions, its limited heterogeneity in melanoma lesions, its high density on melanoma cells, and its restricted distribution in normal tissues (for review, see 10). Fourth, we have availability to use the mouse antiidiotypic MAb MFI 1-30 to an idiotope within the antigen-combining site of the syngeneic anti-HMW-MAA MAb 225.28. This antiidiotypic MAb bears the mirror image of HMW-MAA, because it induces anti-HMW-MAA antibodies in allogeneic and xenogeneic combinations (Chattopadhyay, P., S. V. Kaveri, J. Rosenberg, N. Byars, J. Starkey, S. Ferrone, and S. Raychadhuri. Submitted for publication.) The aim of this paper is to describe the results of two clinical trials with anti-1. Abbreviations used in this paper: HMW-MAA, high-molecularweight-melanoma-associated antigen; PBS-T20, PBS supplemented with 0.05% Tween 20; TAA, tumor-associated antigen.

SummaryAccumulation of α-synuclein (α-syn) into insoluble aggregates occurs in several related disorders collectively referred to as synucleinopathies. To date, studies have used neural stem cells (NSCs) to examine questions about α-syn propagation, but have overlooked the therapeutic potential of NSC transplantation to modulate cognition in disorders such as dementia with Lewy bodies or Parkinson’s disease dementia. Here, we show that striatal transplantation of NSCs into aged α-syn transgenic mice significantly improves performance in multiple cognitive and motor domains. This recovery is associated with NSC expression of brain-derived neurotrophic factor (BDNF), which restores depleted levels and modulates dopaminergic and glutamatergic systems. Most importantly, transplantation of BDNF-depleted NSCs fails to improve behavior, whereas AAV-mediated BDNF delivery mimics the benefits of NSC transplantation, supporting a critical role for this neurotrophin in functional improvement. Thus, NSC transplantation could offer a promising approach to treat the understudied yet devastating cognitive components of many synucleinopathies.

No abstract

Current behavioral measurements for motor impairment are not consistently sensitive in rodent models of partial nigrostriatal dopamine (DA) depletion. In addition to exploratory and somatosensory behavior, motor skills that are thought to be directly translatable to human Parkinson's disease patients are assessed. However, many of these motor tests require the training and learning of particular tasks, so it cannot be determined whether impairments are due to motor or to learning deficit. Therefore, we have quantified multiple temporal and spatial indices of gait dynamics in a model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced partial nigrostriatal lesioning using a treadmill apparatus requiring no prior training. Three days following the cessation of progressively increased MPTP administration, rearing and foot-fault behaviors showed significant deficit. Ten days after the final MPTP injection, gait dynamics were assessed and indicated differences between MPTP- and vehicle-treated animals. The major significant changes were in stride length, frequency, duration, and number of steps. Three weeks following a progressively increased dose of MPTP (administered 5 days per week over the course of 4 weeks), mice showed a 63% decrease in tyrosine hydroxylase-immunoreactive (TH-ir) nigrostriatal neurons in the substantia nigra pars compacta and a 72% decrease in TH-ir terminals in the caudate-putamen. This suggests that there is a continued effect of progressively increased MPTP on nigrostriatal DA neurons, correlated with rearing and foot-fault behaviors and further characterized by differences in temporal and spatial measurements of gait dynamics.