AUTHOR=Paolone Giovanna 

TITLE=From the Gut to the Brain and Back: Therapeutic Approaches for the Treatment of Network Dysfunction in Parkinson's Disease

JOURNAL=Frontiers in Neurology

VOLUME=Volume 11 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2020.557928

DOI=10.3389/fneur.2020.557928

ISSN=1664-2295

ABSTRACT=Parkinson's disease (PD) is a complex, multisystem progressive, degenerative disorder characterized by severe, debilitating motor dysfunction, cognitive impairments, and mood disorders.  While pre-clinical research has traditionally focused on the motor deficits resulting from the loss of nigrostriatal dopaminergic neurons, up to two thirds of PD patients present separate and distinct behavioral changes.  Loss of basal forebrain cholinergic neurons occurs as early as the loss of dopaminergic cells and contributes to the cognitive decline in PD. In addition, attentional deficits can limit posture control and movement efficacy caused by dopaminergic cell loss.  Complicating the picture further, intracellular α-synuclein accumulation beginning in the enteric nervous system and diffuses to the substantia nigra through the vagus nerve. It seems that α-synuclein mediates dopamine synthesis, storage and release while its function has not been completely understood.   Treating a complex, multi-stage network disorder such as PD, likely requires a multi-pronged approach.  Here, we describe a few approaches that could be used alone, or perhaps in combination to achieve a greater mosaic of behavioral benefit.  These include (1) using encapsulated genetically-modified cells as delivery vehicles for administering neuroprotective trophic factors such as GDNF in a direct and sustained means to the brain, (2) immunotherapeutic interventions such as vaccination or the use of monoclonal antibodies against aggregated, pathological α-synuclein, (3)  the  continuous infusion of levodopa-carbidopa through an intestinal gel pad to attenuate the loss of dopaminergic function and manage the motor and non-motor complications in PD patients, (4) specific rehabilitation treatment programs for drug-refractory motor complications.