Safinamide - a unique treatment targeting both dopaminergic and non-dopaminergic systems

Dopaminergic replacement therapies are prescribed widely to improve motor problems in Parkinson's disease (PD). However, as the disease progresses, the response to levodopa (l-dopa) doses becomes shorter and patients experience symptom recurrence at the end of the dose effect. These so-called OFF periods may become refractory to treatment, and may become associated with disabling motor fluctuations or dyskinesias. In addition to dopamine, glutamate excitotoxicity, resulting from disturbance of the homeostatic balance of neurotransmitters and elevated extracellular levels of glutamate, is potentially an important therapeutic target. Safinamide has been investigated in phase III clinical trials as adjunct therapy to l-dopa in mid- to late-stage fluctuating PD. Adding safinamide to l-dopa increases the time patients' symptoms are controlled so-called ON time, without increasing troublesome dyskinesia. Although safinamide has dopaminergic actions, recent data have suggested that the long-term effects of safinamide on dyskinesia are related to safinamide state- and use-dependent inhibition of sodium channels and stimulated glutamate release, rather than reduced dopaminergic stimulation. Safinamide's unique dual mechanism of action makes it a valuable treatment option for fluctuating PD patients

Angiotensin type 1 receptor antagonists protect against alpha-synuclein-induced neuroinflammation and dopaminergic neuron death

The loss of dopaminergic neurons and alpha-synuclein accumulation are major hallmarks of Parkinson's disease (PD), and it has been suggested that a major mechanism of alpha-synuclein toxicity is microglial activation. The lack of animal models that properly reproduce PD, and particularly the underlying synucleinopathy, has hampered the clarification of PD mechanisms and the development of effective therapies. Here, we used neurospecific adeno-associated viral vectors serotype 9 coding for either the wild-type or mutated forms of human alpha-synuclein (WT and SynA53T, respectively) under the control of a synapsin promoter to further induce a marked dopaminergic neuron loss together with an important microglial neuroinflammatory response. Overexpression of neuronal alpha-synuclein led to increased expression of angiotensin type 1 receptors and NADPH oxidase activity, together with a marked increase in the number of OX-6-positive microglial cells and expression of markers of phagocytic activity (CD68) and classical pro-inflammatory/M1 microglial phenotype markers such as inducible nitric oxide synthase, tumor necrosis factor alpha, interleukin-1B, and IL-6. Moreover, a significant decrease in the expression of markers of immunoregulatory/M2 microglial phenotype such as the enzyme arginase-1 was constantly observed. Interestingly, alpha-synuclein-induced changes in microglial phenotype markers and dopaminergic neuron death were inhibited by simultaneous treatment with the angiotensin type 1 blockers candesartan or telmisartan. Our results suggest the repurposing of candesartan and telmisartan as a neuroprotective strategy for PD

MAPT H1 haplotype is associated with late-onset Alzheimer's disease risk in APOE epsilon 4 noncarriers: results from the dementia genetics Spanish consortium

The MAPT H1 haplotype has been linked to several disorders, but its relationship with Alzheimer's disease (AD) remains controversial. A rare variant in MAPT (p.A152T) has been linked with frontotemporal dementia (FTD) and AD. We genotyped H1/H2 and p.A152T MAPT in 11,572 subjects from Spain (4,327 AD, 563 FTD, 648 Parkinson's disease (PD), 84 progressive supranuclear palsy (PSP), and 5,950 healthy controls). Additionally, we included 101 individuals from 21 families with genetic FTD. MAPT p.A152T was borderline significantly associated with FTD [odds ratio (OR)=2.03; p=0.063], but not with AD. MAPT H1 haplotype was associated with AD risk (OR=1.12; p=0.0005). Stratification analysis showed that this association was mainly driven by APOE epsilon4 noncarriers (OR=1.14; p=0.0025). MAPT H1 was also associated with risk for PD (OR=1.30; p=0.0003) and PSP (OR=3.18; p=8.59 × 10-8) but not FTD. Our results suggest that the MAPT H1 haplotype increases the risk of PD, PSP, and non-APOE epsilon4 AD