Improved mitochondrial function in brain aging and Alzheimer disease - the new mechanism of action of the old metabolic enhancer piracetam

Abstract

Piracetam, the prototype of the so-called nootropic drugs' is used since many years in different countries to treat cognitive impairment in aging and dementia. Findings that piracetam enhances fluidity of brain mitochondrial membranes led to the hypothesis that piracetam might improve mitochondrial function, e.g., might enhance ATP synthesis. This assumption has recently been supported by a number of observations showing enhanced mitochondrial membrane potential, enhanced ATP production, and reduced sensitivity for apoptosis in a variety of cell and animal models for aging and Alzheimer disease. As a specific consequence, substantial evidence for elevated neuronal plasticity as a specific effect of piracetam has emerged. Taken together, this new findings can explain many of the therapeutic effects of piracetam on cognition in aging and dementia as well as different situations of brain dysfunctions.

Keywords: aging; alzheimer's disease; mitochondrial dysfunction; oxidative stress; piracetam.

Figure 1

Piracetam reduces measures of mitochondrial dysfunction in NMRI mice – higher sensitivity in aged mice 2–3 months old and 22–24 months old NMRI mice were treated for 14 days with 0.5 g piracetam/kg in 0.9% NaCI solution p.o. once daily for 2 weeks. Control animals received 0.9% NaCI solution alone. All data are modified after Keil et al. (2006). (A) Dissociated brain cells were isolated and MMP was detected. The MMP was significantly reduced in old animals (22 months) and protected by Piracetam. Data are expressed as mean ± SEM (n = 6–8) *p < 0.05 piracetam treated old animals vs. aged controls. (B,C) Effects of aging and treatment with piracetam on SOD, and GPx in young and old animals. Activities of antioxidant enzymes are increased in aged mice. Treatment with piracetam reduces the enzyme activities significantly in old mice. Data are expressed as mean ± SEM (n = 7). *p < 0.05 piracetam treated old animals vs. aged controls.

Figure 2

Piracetam improves measures of mitochondrial function in tgAPP mice. (A) Animals were treated for 14 days with 0.5 g piracetam/kg in 0.9% NaCI solution p.o. once daily for 2 weeks. Control animals received 0.9% NaCI solution alone. All data are modified after Kurz et al. (2010). The MMP was significantly reduced in tgAPP mice. Piracetam treatment normalizes the MMP to non-tgAPP levels. Data are expressed as mean ± SEM (n = 7–8). +p < 0.05 control non-tgAPP vs. control tgAPP, *p < 0.01 piracetam treated tgAPP vs. tgAPP control; Student's unpaired t-test. (B) ATP levels were also significantly impaired in tgAPP mice. In contrast, piracetam treatment increases ATP levels not only in tgAPP animals but also in control animals. Data are expressed as mean ± SEM (n = 7-8). *p < 0.05 control non-tgAPP vs. piracetam treated non-tgAPP; +p < 0.05 control non-tgAPP vs. control tgAPP, *p < 0.01 piracetam treated tgAPP vs. tgAPP control; Student's unpaired t-test.

Figure 3

Piracetam ameliorates elevated Aβ production following mitochondrial dysfunction. (A) Normalized Aβ levels were quantified in brain homogenates from non-tg littermate and tgAPP mice (3 months old). **p < 0.01 piracetam treated tgAPP vs. control tgAPP; student's unpaired t-test. (B) Piracetam reduces nitrosative stress induced elevation of Aβ in APPwt HEK293 cells. Cells were preincubated for 24 h with piracetam (1 mM) and stressed for additional 24 h with SNP (0.5 mM). Data are expressed as mean ± SEM (n = 3–4). +++p < 0.001 APPwt HEK293 control cells vs. cells treated with SNP, *p < 0.01 APPwt HEK293 cells stressed with SNP 0.5 mM vs. stressed cells preincubated with piracetam; Student's unpaired t-test. (C) Piracetam ameliorates nitrosative stress induced reduction of mitochondrial membrane potential. Cells were preincubated for 24 h with piracetam (1 mM) and stressed for additional 24 h with SNP (0.5 mM). Data are expressed as mean ± SEM (n = 6). All data are modified after Kurz et al. (2010). **p < 0.01 APPwt HEK293 cells stressed with SNP 0.5 mM vs. stressed cells preincubated with piracetam, Student's unpaired t-test.

Figure 4

Piracetam improves neuritogenesis following Aß exposure. (A) PC12 cells were treated over 6 days with NGF 50 ng/ml in the presence of oligomeric Aβ 1 μM. Piracetam 1 mM was added and the effects on neurite outgrowth were investigated. (B) APPsw PC12 cells were treated over 6 days with NGF 50 ng/ml in the presence or absence of piracetam 1 mM and neurite outgrowth was measured. In the presence of different NGF concentrations (1–50 ng/ml) piracetam improved the neurotrophic effect of NGF in APPsw cells. All data are modified after Kurz et al. (2010). Data are expressed as mean ± SEM (n = 6–7) **p < 0.01, ***p < 0.001 vs. the respective control, two-way anova with bonferroni post test.

Figure 5

Piracetam improves cognitive function in men after hypoxia. The ability of 12 healthy volunteers to concentrate in a low oxygen pressure tank was assessed by measuring errors in a visual attention test in a placebo-controlled crossover trial in which volunteers were given 4.8 g piracetam daily for 4 days and 7.2 g on the fifth day. Depending on the time of hypoxia, errors were observed. Error number was significantly reduced by piracetam treatment, especially for the longer hypoxic period. Data are modified from Demay and Bande (1980).

Figure 6

Piracetam improves cerebral hypoperfusion-induced deficits in learning and memory. Rats were treated for 30 days with piracetam 600mg/kg per day after ligature of bilateral carotid arteries. The Sham-operated group was only treated with saline without induction of hypoperfusion. The Morris water maze was performed with four trials per day during 5 days for the acquisition test (A), and performed with four trials on day 6 without the platform retention test (n = 10 ± SEM) (B). Representative examples of typical swim-tracking pathways in probe trial on training day 6 no platform (C). (n = 10 ± SEM). Data are reproduced from He et al. (2008) with permission. *p < 0,01 vs. Sham-operated, and #p < 0.05 vs. control hypoperfusion. Tukey's test following a repeated ANOVA.

Figure 7

Piracetam improves LTP after cerebral hypoperfusion in CA3 synapses. Changes in LTP after ligature of carotoids induced as described by He et al. (2008). The animals were treated in the Sham-operated group (I, IV) and in the HP group (II, V) for 30 days with saline, and in the piracetam group (III, VI) with 600 mg/kg per day. (A) LTP was blocked in the HP group and improved in the piracetam treated group. (B) Improvement of the population spike (PS) by piracetam (n = 7–8 ± SEM). Data are reproduced from He et al. (2008) with permission. *p < 0,01 vs. Sham-operated, and #p < 0.05 vs. control hypoperfusion. One-way ANOVA followed by Fisher LSD test.