1.Current management of the cognitive dysfunction in Parkinson's disease: how far have we come?
Vale S1. Exp Biol Med (Maywood). 2008 Aug;233(8):941-51. doi: 10.3181/0707-MR-193. Epub 2008 Jun 5.
Parkinson's disease (PD) clinical features comprise both motor and nonmotor manifestations. Among the nonmotor complications, dementia is the most important. Approximately 40% of PD patients are affected by cognitive impairment. Remarkably, in addition to age, dementia is an independent predictor of mortality, whereas age at onset of PD and severity of neurological symptoms are not. In this review, I summarize the current knowledge of the pathogenesis of the PD cognitive impairment in relation to the therapies presently accessible and those that could become strategic in the near future. It is hypothesized that patients with PD show two components of cognitive dysfunction (CD): a generalized profile of subcortical dementia (PDsCD), and an overlapped pattern suggesting specific prefrontal damage with CD (PDpFCD). PDsCD is associated with structural neocortical/subcortical changes in the brain (in frontal, parietal, limbic, and temporal lobes, as well as in midbrain structures).
2.Evaluation of the pro-cognitive effects of the AMPA receptor positive modulator, 5-(1-piperidinylcarbonyl)-2,1,3-benzoxadiazole (CX691), in the rat.
Woolley ML1, Waters KA, Gartlon JE, Lacroix LP, Jennings C, Shaughnessy F, Ong A, Pemberton DJ, Harries MH, Southam E, Jones DN, Dawson LA. Psychopharmacology (Berl). 2009 Jan;202(1-3):343-54. doi: 10.1007/s00213-008-1325-2. Epub 2008 Sep 16.
RATIONALE: Positive allosteric modulators of the glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor do not stimulate AMPA receptors directly but delay deactivation of the receptor and/or slow its desensitisation. This results in increased synaptic responses and enhanced long-term potentiation. Thus, it has been suggested that such compounds may have utility for the treatment of cognitive impairment.
3.Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers.
Wezenberg E1, Verkes RJ, Ruigt GS, Hulstijn W, Sabbe BG. Neuropsychopharmacology. 2007 Jun;32(6):1272-83. Epub 2006 Nov 22.
Ampakines act as positive allosteric modulators of AMPA-type glutamate receptors and facilitate hippocampal long-term potentiation (LTP), a mechanism associated with memory storage and consolidation. The present study investigated the acute effects of farampator, 1-(benzofurazan-5-ylcarbonyl) piperidine, on memory and information processes in healthy elderly volunteers. A double-blind, placebo-controlled, randomized, cross-over study was performed in 16 healthy, elderly volunteers (eight male, eight female; mean age 66.1, SD 4.5 years). All subjects received farampator (500 mg) and placebo. Testing took place 1 h after drug intake, which was around Tmax for farampator. Subjects performed tasks assessing episodic memory (wordlist learning and picture memory), working and short-term memory (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Information processing was assessed with a tangled lines task, the symbol digit substitution test (SDST) and the continuous trail making test (CTMT).
4.Differential effects of AMPA receptor potentiators and glycine reuptake inhibitors on antipsychotic efficacy and prefrontal glutamatergic transmission.
Jardemark K1, Marcus MM, Malmerfelt A, Shahid M, Svensson TH. Psychopharmacology (Berl). 2012 May;221(1):115-31. doi: 10.1007/s00213-011-2554-3. Epub 2011 Nov 9.
RATIONALE: The α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor positive allosteric modulators (AMPA-PAMs), Org 24448 and Org 26576, and the glycine transporter-1 (GlyT-1) inhibitor Org 25935 are developed for treatment of schizophrenia.