Similar to the situation in man, piracetam has also been shown to improve cognitive function in animals, but its mode of action is not yet finally known Winblad, This assumption was later supported by observations that piracetam specifically enhances membrane fluidity in aged brain material, showing no effect at all in membranes from young brains Muller et al.

This unique mechanism of action could be explained by the specific binding to the polar head-structures of membrane phospholipids leading to a more flexible arrangement of the fatty acid side chain structure, which got more rigid due to lipid peroxidation in aging or other situations associated with enhanced oxidative stress Peuvot et al.

Since these effects were observed at concentrations also needed in pharmacological experiments to improve cognition Saletu et al. However, the mechanism of these effects and its possible relationship to mitochondrial function remained obscure.

As a specific feature of piracetam and other similar compounds, beneficial effects on cognition are usually associated with impaired brain function such as aging, hypoxia, glucose deprivation, injuries, or even neurodegeneration. As all the pathological conditions mentioned above are typically associated with the vicious cycle between enhanced oxidative stress — elevated reactive oxygen species ROS production — mitochondrial damage — reduced energy supply — enhanced ROS production Leuner et al.

In both situations, similar but also variant alterations of mitochondrial function are present Leuner et al. Like other differentiated tissues, the central nervous system is profoundly affected by aging and reacts to aging by a decline of several physiological abilities including sensory, motor, emotional, or cognitive functions Sastre et al.

Aging brain cells experience increasing amounts of oxidative stress, perturbed energy homeostasis, accumulation of damaged proteins, lesions in their nucleic acids and are characterized by impaired function of signaling mechanisms and altered gene expression.

These changes were significantly exacerbated in neurodegenerative disorders and amplified in vulnerable neuronal populations be disease related processes such as accumulation of damaged proteins, e.

Beside the described dysfunctions, mitochondrial perturbations are strongly associated with aging. Mitochondria play a central role in producing ATP as the central source of cellular energy and are critical regulators of programmed cell death during aging Sastre et al.

In the brain of AD patients, defective energy metabolism and early defects in glucose utilization were observed already many years before Munch et al. Moreover, the AD brain is specifically marked by accumulation of the misfolded proteins Aß and hyperphosphorylated tau, both contributing together with aging-related deficits to severe neurodegenerative alterations, such as the loss of synapses and neurons, atrophy, and the selective depletion of neurotransmitter systems e.

At the mitochondrial level, complex I and complex IV seem to be specifically affected, where tau pathology mainly impairs complex I activity, and Aß complex IV activity Eckert et al.

One of the earliest changes observed in AD is synaptic failure which already starts in patients with mild cognitive impairment MCI and manifests during the disease process Selkoe, Mitochondria are key players in synaptic plasticity providing the necessary energy Mattson et al.

The observed mitochondrial deficits result in enhanced oxidative stress. Importantly, mitochondrial dysfunction and reduced bioenergetics occur early in pathogenesis and precede the development of plaque formation Hauptmann et al.

While the concept of Aß-induced mitochondrial dysfunction as a major functionally relevant pathomechanism in AD has received substantial support over the last decade, improving mitochondrial function as a target for new drug development has rather not, as most interest has been directed to drugs leading to reduced Aß load Lemere et al.

However, as several compounds out of those disease-modifying drug classes have recently failed to show clinical effectiveness in AD trials Gura, , a report about substantial therapeutic effects of dimebon in a 1-year clinical trial Doody et al. Quite interestingly, although originally used as an antihistaminic drug, dimebon was later characterized as a mitochondrial stabilizer with rather similar properties as reported for piracetam in the present communication Bachurin et al.

The concept of using mitochondrial protection as treatment strategy for dementia has recently been further supported by a preliminary report about again substantial clinical improvement in AD patients treated with methylene blue Gura, Importantly, this drug not only has been shown to enhance cognitive functions in several animal studies associated with elevated oxygen consumption, but also seems to enhance mitochondrial function by activating complex I and IV activities at the cellular level Callaway et al.

The close association and common basis of oxidative stress and mitochondrial dysfunction in brain aging and age-related neurodegenerative disorders like AD see the previous chapters explains that several antioxidants have a long history as possible treatments for AD and even have been and are used in this context.

Initially mainly Vitamin E or Vitamin C or the combination of both was investigated Bastianetto and Quirion, ; Farlow et al. While both at high concentrations definitively show antioxidant properties in vitro and in vivo , their therapeutical benefit to improve or even prevent cognitive impairment in the elderly is at present seen rather critically.

Another important class of naturally accruing antioxidant are flavonoids or other polyphenols, which also are fairly good antioxidants which reduced oxidative stress in vitro and in vivo.

Flavonoids also improve mitochondrial dysfunction and seem to have therapeutical benefit for long-term treatment of age-related cognitive impairment animals and men Schmitt-Schillig et al. The significant reduction of the risk in getting AD by Mediterranean diet is very likely explained to an impotent part by the high daily intake of flavonoids Scarmeas et al.

In general, even if the effectiveness of those natural occurring antioxidants to protect against AD seems to be limited, they seem to be the major players of diet in reducing oxidative stress and acting as a second however considerably weaker defense system.

Another case of a herbal drug is the standardized Ginkgo biloba extract EGb , which has been used for many years as a prescription or OTC drug in many countries to treat aging-related cognitive disorders including AD Christen and Maixent, While the flavonoid fraction seems to be mainly responsible for the free radical scavenging properties, several terpene lactones Ginkgolides, Bilobalide show substantial mitochondria-protecting properties Abdel-Kader et al.

Oxidative stress usually accumulates in aged or diseased brain tissue over years or even decades due to the vicious cycle between increased ROS, and enhanced mitochondrial dysfunction Floyd and Hensley, Within this system, mitochondria play a crucial role as their impaired function not only leads to reduced ATP production and finally enhanced apoptosis Mattson, ; Mattson et al.

Accordingly, due to our initial findings of piracetam enhancing mitochondrial membrane fluidity Eckert et al. To investigate this assumption, we used different cell models in tissue culture and induced experimentally oxidative stress using different approaches to mirror within hours or a few days what is usually seen in aged or diseased brains at the end of the life span.

Mitochondrial function was assessed by monitoring mitochondrial membrane potential MMP using specific membrane dyes, by measuring ATP production, and the release of proapoptotic factors Keil et al.

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.

once daily for 2 weeks. Control animals received 0. All data are modified after Keil et al. A Dissociated brain cells were isolated and MMP was detected. The MMP was significantly reduced in old animals 22 months and protected by Piracetam.

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.

Beside the use of H 2 O 2 in some initial experiments, we usually induced oxidative stress by the NO donor sodium nitroprusside SNP , due to the important role of nitrosative stress in AD Keil et al. In PC12 cells, SNP, led to a reduction of MMP and ATP levels.

Under basal conditions without additional SNP damage, piracetam did not affect both alterations even at rather high concentrations. However, piracetam was able to reduce both measures of mitochondrial dysfunction after pre- and post-incubation Keil et al.

Another stressor, serum deprivation also leads to a decrease of mitochondrial membrane potential MMP and a decrease of ATP levels in neurons. Additionally, serum like glucose deprivation in PC12 cells causes peroxidation of their cell membrane lipids, decreases intracellular SOD activity, and enhances apoptosis in PC12 cells Keil et al.

Interestingly, piracetam was able to protect MMP against cellular stress following serum deprivation. Under this condition, piracetam completely restored ATP levels, while at lower serum concentrations only a partial restoration was seen Keil et al.

As mentioned before, complex I and complex IV functions are impaired in aging and AD. Thus, the possible efficacy of piracetam to protect individual complexes of the mitochondrial respiratory chain after treatment with specific complex inhibitors was also investigated.

Complexes I, II, and III were already protected at concentrations as low as μM piracetam, while a significant protection of complexes IV and V was observed at a concentration of μM piracetam Keil et al.

This broad activity of piracetam is in line with the assumptions that improvement of complex activity might be due rather to its fluidity enhancing properties at mitochondrial membranes rather than by specific effects at the individual complexes. This is also supported by the data of Zhang et al. It is very important to note that the beneficial effects of piracetam have not only been seen at the level of MMP but also in using several other measures of mitochondrial function since MMP alterations are not always directly connected with changes of mitochondrial function Cao et al.

As already mentioned, a major link between the mitochondrial defects of our brain accumulating during decades of aging and the specific Aß related toxicity in AD seems to be oxidative stress induced by Aß as well as Aß induced impairment of mitochondrial function, e.

This very slow process can experimentally be investigated by inducing mitochondrial dysfunction in cells in tissue culture following incubation with extracellularly applied Aß Kurz et al.

Since Aß 1—42 is presently considered as the main toxic Aß species, we used this peptide and several experimental cell models PC12 cells, HEK cells, dissociated mouse brain cells to study possible protective effects of piracetam on mitochondrial deficits.

When PC12 cells were treated with fibrillar Aß 1—42 10 nM for 24 h a reduction of MMP was observed as described previously by our group Keil et al.

The addition of piracetam 30 min after Aß 1—42 substantially protected MMP at concentrations already beginning with 0. Comparable protective effects of piracetam were observed for dissociated brain cells of Naval Medical Research Institute NMRI mice following incubation with fibrillar Aß 1— In both cell types, piracetam alone has no effect on MMP.

We used aged NMRI mice which are bread in our animal facilities not only showing clear cognitive impairment but also several measures of oxidative stress, and mitochondrial dysfunction at an age around 20 months including a decreased MMP compared to young mice Müller et al.

Piracetam treatment for 14 days normalized MMP in aged mice, while similar treatment of young animals had no effect Figure 1.

On the other hand, a similar piracetam treatment not only protected brain cells of aged but also young mice against oxidative stress induced in vitro by addition of H 2 O 2 , SNP, or Aß 1— Even if brain cells of young mice treated with piracetam also showed some benefit from piracetam treatment, aged animals usually responded most Figure 1.

Antioxidative enzymes are the primary defense mechanism to protect biological macromolecules from oxidative damage, and are upregulated in aged mouse brain as an adaptive response to oxidative stress.

Therefore, we investigated the effect of piracetam treatment on the activities of superoxide dismutase SOD , glutathione peroxidase GPx , and glutathione reductase GR in young mice 2—3 months old and old mice 22—24 months old.

We confirmed a significant increase in GPx and GR activity in aged mice compared to young mice. The activity of SOD had also a tendency to increase with age. Piracetam treatment decreased the activities of all three enzymes in aged mice nearly to the level of young animals.

In young mice, a only small and not significant decrease of antioxidative enzymes could be observed Figure 1. Unfortunately, both studies did not report glutathione levels, which also has a relevant role in regulating mitochondrial function Jha et al.

Isolated brain cells of mice overexpressing mutated human amyloid precursor protein tgAPP show significant reductions of MMP and ATP synthesis relative to non-transgenic littermate controls confirming previous observation from our group Hauptmann et al.

Similar piracetam treatment 0. As reported earlier Blanchard et al. A related observation showing reduced Aß levels in the plasma of geriatric patients treated with piracetam was published by Blasko et al.

In order to investigate if this effect of piracetam on Aß levels might also be associated with improved mitochondrial function, we used APPwt HEK cells stably overexpressing human APP showing moderately enhanced Aß levels Keil et al. Piracetam lowered Aß levels under basal conditions Kurz et al.

In agreement with other findings Guglielmotto et al. In addition, piracetam improves mitochondrial function under the same conditions in APPwt HEK when Aß generation is decreased Figure 3.

Figure 2. Piracetam improves measures of mitochondrial function in tgAPP mice. A Animals were treated for 14 days with 0. All data are modified after Kurz et al. The MMP was significantly reduced in tgAPP mice.

Piracetam treatment normalizes the MMP to non-tgAPP levels. 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.

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. B Piracetam reduces nitrosative stress induced elevation of Aβ in APPwt HEK cells.

Cells were preincubated for 24 h with piracetam 1 mM and stressed for additional 24 h with SNP 0. C Piracetam ameliorates nitrosative stress induced reduction of mitochondrial membrane potential.

In agreement with the pronounced loss of neurites and synapses in AD brain as one of the functionally most relevant histopathological lesions Selkoe, ; Lacor et al.

Oligomeric Aß seems to be more active than fibrillar Aß Lacor et al. In agreement with these observations, the addition of oligomeric Aß 1—42 1 μM to nerve growth factor NGF treated PC12 cells reduces neuritic length significantly.

When the same experiment was carried out in the presence of piracetam 1 mM , the negative effect of oligomeric Aß 1—42 was completely inhibited. In agreement with the assumption that enhanced oxidative stress might explain the Aß induced reduction of neuritic outgrowth Guglielmotto et al.

Again, piracetam ameliorates this negative effect significantly under conditions of optimal NGF stimulation Figure 4. A reduction of neuritic outgrowth depending on Aß load was also observed in our PC12 cells transgenic for human APP, where we observed a reduction of neuritic length, which could be substantially ameliorated by piracetam Figure 4.

Figure 4. Piracetam improves neuritogenesis following Aß exposure. Piracetam 1 mM was added and the effects on neurite outgrowth were investigated. the respective control, two-way anova with bonferroni post test.

The data presented clearly show that piracetam protects mitochondria against different conditions associated with oxidative stress including aging.

This is not surprising, since the conditions used to induce oxidative stress in vitro are not pathophysiological but rather aggressive, in contrast to the small and slowly occurring changes induced by aging, which however were sometimes completely reversed by piracetam treatment. This was also the case for the adaptive elevation of antioxidant enzyme activities.

When mild conditions were used in vitro e. partial serum deprivation , a complete protection of mitochondrial function was seen by piracetam treatment in PC12 cells. Moreover, piracetam was highly effective in vivo in pathophysiologically relevant situations of brain dysfunction.

Piracetam does not possess radical scavenging properties Keil et al. Thus, it seems quite likely that piracetam acts directly at the mitochondrial level, presumably by improving mitochondrial membrane properties.

This is also supported by our observation that in several experiments protective effects were also seen in the recovery phase, when the oxidative stressor was already removed.

Moreover, experiments from our lab also indicate comparable effects of piracetam on isolated mouse brain mitochondria of animals treated with piracetam.

Thus, it is quite likely that similar effects are also taking place in the brain of piracetam treated patients. While the interaction of piracetam with neuronal membranes shows little changes of membrane properties under normal conditions, it significantly enhances reduced membrane fluidity, for example, in the aging or even Alzheimer brain.

All the conditions associated with positive effects of piracetam on mitochondrial function in the experiments reviewed above also seem to be associated with decreased membrane fluidity mainly due to enhanced lipids peroxidation.

Thus, it seems quite plausible that piracetam improves mitochondrial function by enhancing fluidity of mitochondrial membranes, which seems to be a critical factor regulating mitochondrial function.

However, direct proof for this mechanism still needs to be shown. Piracetam was originally developed as a cyclic derivative of gamma-aminobutyric acid GABA to treat anxiety. Piracetam not only did not have antihistaminic or anticholinergic properties, but even did not show any central activity like sedation, stimulation, or influence on autonomic function.

However, as a rather new spectrum of pharmacological properties piracetam did facilitate interhemispheric transfer, enhanced the cerebral resistance to noxious stimuli like hypoxia and, most importantly, it enhanced or facilitated learning and other cognitive functions Giurgea, These cognition improving properties still represent the basis of the present therapeutical use of piracetam in many countries all over the world in the whole spectrum of geriatric memory disorders, in cases of impaired cognitive functions after head injuries, and also in vertigo.

Even if piracetam can facilitate learning and other cognitive functions under normal conditions e. Since these preclinical and clinical data form the link between mitochondrial protection as major preclinical mechanism of action and the clinical efficacy of piracetam in a large variety of diverse groups of older subjects with cognitive impairment, some of these data will be reviewed shortly.

Two older studies have investigated the cognition improving effects of piracetam in young volunteers under mild hypoxia as a pharmacological model to mirror impaired brain function as seen in aging or dementia Demay and Bande, ; Saletu et al. The data from Demay and Bande are given in Figure 5 showing considerably less errors in a memory task under hypoxia following 5 days of piracetam treatment with 4.

Hypoxia induced cognitive but also biochemical and physiological deficits mirroring the situation in dementia has also been used in a very recent study in rats He et al.

In this study, chronic cerebral hyperfusion was induced by ligature of bilateral common carotid arteries leading to acute but also subacute structural and functional brain deficits. Most importantly, spatial memory performance Morris Water maze was substantially impaired and showed pronounced improvement by piracetam treatment mg per day starting after surgery Figure 6.

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Close Thanks for visiting. We also highlight some of the limitations to the use of food-based nootropics and suggest ways in which they can be better employed in the clinical management of age-related cognitive decline. Conclusion: While it is known that the human brain endures diverse insults in the process of ageing, food-based nootropics are likely to go a long way in mitigating the impacts of these insults.

Further research is needed before we reach a point where food-based nootropics are routinely prescribed.