Look I found something interesting … I’ve already mentioned it before.
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[b]Background: Discovery of neurotrophic factors - emblematic: the nerve growth factor (NGF) - resulted in better approaching central nervous system (CNS) lesions. Recently, another crucial property has been unveiled: their rather unique pleiotropic effect. Cerebrolysin is a peptide mixture that penetrates the blood-brain barrier in significant amounts and mimics the effects of NGF.
Methods: Comparative analysis: Cerebrolysin treated (10 ml x 2/ day, i.v. x 3 weeks) vs. non-treated, in patients (all received aside, a rather equivalent complementary, pharmacological and physical, therapy). Two lots of patients, admitted in our Physical & Rehabilitation (neural-muscular) Medical - PR(n-m)M - Clinic Division, during 2007-2009: 69 treated with Cerebrolysin (22 F, 47 M; Average: 59.333; Mean of age: 61.0 Years old; Standard deviation 16.583) and 70 controls (41 F, 29 M; A: 70.014; M.o.a.: 70.5 Y.o.; S.d.: 6.270) were studied. The total number of assessed items was 13: most contributive in relation with the score of Functional Independence Measure at discharge (d FIM), were: admission (a FIM), number of physical therapy days (PT), number of hospitalization days (H), age (A) and - relatively - days until the first knee functional extension (KE). Concomitantly, the main/ key, focused on neuro-motor rehabilitative outcomes, functional/analytical parameters, have been assessed regarding the speed in achieving their functional recovery.
Results: Concerning d FIM, there have not been objectified significant differences between the two lots (p=0.2453) but regarding key, focused on neuro-motor rehabilitative outcomes, functional/analytical parameters: KE (p=0.0007) and days until the first time recovery of the ability to walk between parallel bars (WPB - p=0.0000) – highly significant differences in favor of Cerebrolysin lot resulted.
Conclusion: Cerebrolysin administration, as neurorehabilitative outcomes, proved to hasten, statistically significant, especially the recovery of some critical, for standing and walking, parameters. Thus encouraged, we have now initiated a comprehensive national, 5 year retrospective, multi-centre - based on unitary data acquisition frame and mathematical apparatus – study, to evaluate the results of the treatment with Cerebrolysin in traumatic brain injuries (TBI).
In 1986, Rita Levi-Moncalcini (from The Cellular Biology Institute, Rome, Italy) and Stanley Cohen (from the Vanderbilt University School of Medicine, Nashville, USA) received the Nobel Prize for discovering neurotrophic factors: the nerve growth factor - NGF - respectively, the epidermal growth factor - EGF.
Since then, many other neurotrophic factors have been identified: they are polypeptides, naturally synthesized by all types of cells within the CNS and also by other tissues. Their activity is essential for the NS development (they stimulate cell proliferation and differentiation, respectively axonal and dendritic growth), for the neural cells’ natural survival in the absence of injury/resistance to noxious factors and for their phenotype retaining, during lifetime.
Neurotrophic factors stimulate neural plasticity and synaptic activity, and therefore are important for both: learning processes and for the NS’s impressive ability to spontaneously reorganize and thus, clinical adapt/(limited) self-recover, after different injuries.
The discovery of neurotrophic factors - emblematic: NGF - resulted in better approaching CNS lesions. Recently, another crucial property has been unveiled: their rather unique pleiotropic effect [1] – i.e. a combined, complex neuroprotection and neurotrophicity (including neural plasticity) stimulation.
CNS injuries are divided into two main categories: primary - which occur (mainly) at the moment of a trauma - and secondary ones, that develop after the initial injury, as a consequence of a complex and rather specific to CNS, patho-physiological events’ cascade; they produce effects that may continue for a long time. The secondary injury process (synthetically including: excessive synthesis of nitric oxide and oxidative stress, microglia activation, local inflammation, disturbance of microcirculation, blood-brain barrier dysfunction and the most recently acknowledged ”delayed mechanisms of cell death”[2,3,4,5] ) leads in vicious circles, to disastrous consequences:
- neuronal necrosis;
- neuronal apoptosis;
- scar and/or cyst/ hygroma formation - with further - pathogenic effects on CNS tissue;
- demyelination;
- disruption of morpho-functional nerve pathways (disconnection) and/or functional uncoupling, such as diaschisis.
Thus, minimizing the secondary damage “cascade” could result in maximizing post-injury favorable evolution/recovery, including more rapid and consistent neuro-rehabilitative outcomes.
Therefore, the CNS intimate mechanisms of the secondary injuries are, at present, main targets for modern, including pleiotropic, complex therapies.
CNS main pathways for the secondary damage (occurring in the affected area and in its neighborhood):
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Breakdown of the primary traumatized area’s cells.
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Breakdown of the myelin sheath’s structure.
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Release, from inside the disrupted CNS cells - mitochondria are important sources - of reactive oxygen species (ROS).
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Microglia activation including pro-inflammatory, with subsequent delivery of cytokines from these injured structures and of wall components, as well (together - in vicious circle) with supplementary amounts of ROS - as a result of ROS peroxidation lesions of membranes’ phospholipids (under excessive, post tissue injury - including neural - metabolic, mitochondrial/ cell hyperactivity).
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Oxidative stress - the (hyper) local metabolic generation of ROS and physiological antioxidants’ depletion, with subsequent alteration of some gene expression functions (especially for factors/ transcriptional mechanisms type: NF-kB, PPAR, AP-1) and thus priming, including synthesis sequences, that stimulates production of pro-inflammatory cytokines - especially interleukins IL-1, IL-6 and tumor necrosis factor (TNF) α – respectively, with concomitantly reduction of related molecules synthesis (but with anti-mediator role - for example: IL-2).
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Immune imbalance/inflammation.
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Disorder of local microcirculation and integrity of the blood-brain barrier (with consecutive regional ischemia and edema).
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Electrolyte disorders, including massive edema - CNS tissue swelling - induced by suddenly installed osmolysis (often one of the direct effects of primary injury, too) subsequent to the affected cells which die passively – thus, violent osmolysis is also, in such circumstances, a main necrosis mechanism: in necrosis it is the cellular edema which leads to osmolysis, with the cell passively dying off.
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Increase of the nervous tissue metabolism, including oxygen consumption, thus resulting, in the vicious circle, of its sensitivity to hypoxia and - once more – ischemia.
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Large amounts of tiny molecules - Transient Receptor Potential Member (TRPM) 7 - invade the normal surrounding neurons’ membrane surfaces and very probably, mainly through adenil-cyclase, dramatically enhance their oxidative metabolic activity, resulting in more ROS that propagates the damages to an extensive cell (both) apoptosis and necrosis process, in the unaffected neighborhood, too.
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Resulting in a relative excess of exciting neurotransmitters and massive influx of intracellular (toxic/metabolic destructive) calcium ions (see further).
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Sequential activation of key-role genes, including (most dangerous for a non-regenerating tissue, like CNS – as neurons lack centrosomes) those for apoptosis - triggering the “mechanisms of delayed cell death”: programmed cell suicide and apoptosis-like processes - most recently emphasized, having a longer display and being produced at an intimate level, mainly through metabolic disturbance of aggregated proteins involved in the deep mechanisms of cellular reproductive cycles/ vitality-survival [1,6,7].
Briefly, it is worth to synthetically emphasize some of the main beneficial actions but it also limits/side effects - related to the pleiotropic effect subject matter - of one of the most studied and controversially used - including in CNS acute lesions - drug, with strong anti-inflammatory properties: metilprednisolone (MP). The most important action of MP in the acute stage of injury is to inhibit the lipid peroxidation induced by ROS, thus limiting the secondary damage. The antioxidant effects of MP are not mediated via glucocorticoid receptors: other steroidal anti-inflammatory drugs (SAIDs) do not possess similar antioxidant activity [8].
MP interferes with other neural pathological pathways, too:
decreases the arachidonic acid release;
lowers the cellular inflow of calcium ions and subsequently, the apoptosis processes;
decreases anaerobic metabolism and prevents (toxic) lactate/acidosis accumulation;
minimizes neurofilaments degeneration;
reduces post-traumatic nevrax edema and its compressive consequences;
helps maintaining the neuronal membrane potential and the synaptic transmission.[/b]
