Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Healthcare e-Compendium
A joint initiative of DPSRU & DRSC
Author: Dr. Nitin N Dange
M.S., M.CH. (Neurosurgery), OBNI (USA), FFHU (Japan), Lilavati Hospital & Research Centre, Mumbai
download ArticleAbstract
Cerebral ischemia is known to be one of the most common causes of death worldwide. This is caused when proper amount of oxygen and nutrient rich blood does not reach the brain cells. Although various options are available for the management of such condition, efficiency of these methods is not established. On the other hand, Cerebroprotein Hydrolysate is novel therapy option for the patients suffering from such disorder. It provides faster and better recovery of repairing neurons and their growth than other neurotrophic agents.
Keywords: Cerebroprotein hydrolysate, Cerebral ischemia, Traumatic brain injury, Brain stroke, Management of neurological problem
Introduction
Cerebral ischemia is the most common cause of mortality and morbidity across the globe. It is caused due to restricted flow of oxygen and nutrient rich blood towards brain. The insufficient supply of blood towards brain does not meet its metabolic demand, causing damage to brain cells [1]. This leads to impairment in vision, body movement, speaking and may also lead to unconsciousness, weakness in body and irreversible damage to brain.
Epidemiological Consideration
Strokes are considered to be the major public health concern globally. As per the Global Burden of Diseases (GBD) study in 1990, it was the second leading cause of death worldwide [2]. Subsequent update in 2010 showed the rise of 26 percent in past two decades. With this rising increase in proportionality of mortality, stroke has remained the second leading cause of mortality [3]. According to the study data by GBD (2001) the incidence of stroke is most prevalent in the low and medium income countries [4]. In India, a study showed the cardiac disease, diabetic mellitus, hypertension, smoking, tobacco chewing and low haemoglobin to be associated as the risk factor for incidence of ischemic stroke [5].
What is Cerebral Ischemic Injury?
Cerebral ischemic injury is also known as brain ischemia or ischemic stroke. This is mainly caused due to blockage in artery supplying blood to brain. This leads to depriving the oxygen supply to brain, which causes damage to brain cells. If the blood flow is not restored, the permanent damage to brain cells occurs as a result of cerebralhypoxia.
The damage to brain cells may lead to temporary loss of function, the condition is known as transient ischemic attack (TIA), or mini-stroke. This loss of function can return to normal state by restoring the oxygen rich blood supply to brain. This is characterised by the temporary blockage of cerebral blood flow (CBF) due to formation of blood clots which damages the inner walls of brain vasculature [6]. However, they do not cause any permanent damage but one third of the patients are expected to suffer from cerebral ischemic condition within a year [7].
When the blood flow is interrupted for approximately 10 seconds, it causes unconsciousness; if this interruption is prolonged for few minutes, it may cause irreversible damage to the brain cells. This kind of damage leads to death of brain tissue resulting into loss of brain function permanently. This is known as ischemic stroke.
Ischemic strokes are the most common type of strokes accounting for approximately 87 percent of all strokes, in comparison to 23 percent of haemorrhagic strokes resulting from rupturing of blood vessel inside brain [8].
Types, causes and symptoms of Cerebral Ischemia
Ischemic stroke can effect different regions of the brain. If the effect is confined to a particular region, it comes under focal ischemia. But if the effected region is widespread and encompasses the larger area, this is termed as global ischemia.
The function of the blood vessels in the brain is to provide oxygen and nutrient rich blood to the brain cell to work properly; and carry out a particular and specified task. There are various small capillaries which following a certain path ensures that each and every area of the brain is covered. If these vessels due to any reason get blocked or start bleeding, it causes deprivation of blood to the respective areas leading to malfunctioning or even death of that particular region.
The major cause for cerebral infarction or cerebral stroke is the blockage of blood vessel by the clot of blood or plaque of fat molecules. This situation can arise due to the result of thrombosis, embolism or hypoperfusion; or any other associated condition which may restrict the oxygen supply to brain tissue. Such as high blood pressure, atherosclerosis, high cholesterol, atrial fibrillation, prior heart attack, sickle cell anemia, clotting disorders, congenital heart defects, etc. Other risk factors may be associated with diabetes, smoking, obesity, heavy alcohol misuse, use of certain drugs, such as cocaine or methamphetamines. Anything from trauma to tumour, which may cause blood loss or compression of blood vessel resulting in reduced nutrient and oxygen-rich blood to brain, causes cerebral ischemic strokes.
Symptoms of ischemic stroke depends on which part of the brain is affected. But the common one expressed by patients are vision problems (such as blindness in one eye or double vision), weakness (or paralysis in limbs, which may be on one or both sides), dizziness, vertigo, confusion, loss of coordination, drooping of face on one side, slurred speech, loss of consciousness, sudden or strong headaches. Once the symptoms are observed it is necessary to take immediate action to prevent permanent damage of brain tissues.
Pathophysiology of Neurons
Various mechanism underlying the cerebral ischemia are known, as follows:
1. Excitotoxicity and apoptosis/necrosis
Glutamate, the most abundant excitatory neurotransmitter in the brain, is a major contributor to cerebral ischemia-induced excitotoxicity (excitatory amino acids-induced neurotoxicity) and subsequent apoptosis/necrosis [9]. Cerebral ischemia alone can induce overexpression of the death receptor ligands (i.e., tumour necrosis factor (TNF)-α and FasL), as a result of serine/threonine-protein kinase 1-mediated neuronal necroptosis [10].
Furthermore, enhanced expression of c-Jun N-terminal kinase (JNK, a stress-activated protein kinase) after cerebral ischemia can activate Fas- and Bim-mediated pro-apoptotic signals leading to neuronal cell death [11, 12].
2. Reperfusion injury and neuro-inflammation
Reperfusion injury occurs when a tissue/organ encounters deprivation of blood supply followed by a restoration of blood flow to the ischemic area. This however, causes secondary injury due to excessive formation of reactive radical oxide species (ROS) and/or peroxynitrite and activation of the immune system [13, 14].
In terms of ischemia induced neuro-inflammation, infiltrating immune cells release inflammatory mediators to recruit multiple immune and glia cells. Moreover, pro-inflammatory cytokines increase neurotoxic molecules and free radicals (i.e., ROS), reactive nitrogen species, cyclooxygenase-2 and inducible nitric oxide synthase to cause secondary neuronal cell death [15, 16].
Damage associated molecular patterns, such as high-mobility group box1 protein and ATP are released from the cytoplasm upon tissue injury and/or cell death to initiate series of innate immune responses, as a result of excessive production of pro-inflammatory cytokines/chemokines, which causes peroxynitrite- and ROS-mediated lipid peroxidation, DNA damage and cell dysfunction/death [17].
3. Impaired axonal regeneration
One of the major hallmarks of cerebral ischemia is the inherent glial scar formation. Glial scar (a tissue barrier) is formed by reactive astrocytes, microglia, and infiltrating immune cells to protect survival neurons from the harmful environment (i.e., nitric oxide toxicity and glutamate-induced cellular excitotoxicity) [18].
However, the immune-reactive cells, in particular astrocytes, become hypertrophic and release chondroitin sulfate proteoglycans (an inhibitory extracellular molecule) in response to cerebral ischemia [19], which restricts axonal regeneration and neuronal survival via RhoA/ROCK-mediated pathways [20].
In addition to glial scar, myelin (the laminated membrane structure that surrounds the axon) is also responsible for the failure of axonal regeneration. Numerous studies have shown that myelin-associated glycoproteins, such as oligodendrocyte-myelin glycoprotein and nogoA are actually detrimental to axonal regeneration and sprouting after cerebral ischemia [21].
Current Options for the Management of Cerebral Ischemia
Legions formed in brain due to stroke are classified into two parts – the ischemic core and the surrounding penumbra [22]. The irreversible cell death occurs in ischemic core area, while the studies on management are targeted to prevent neuronal cell death in the hypo-perfused penumbra region [23]. Details on these studies of neuro-regenerative agents (Table 1) and other novel factors/therapies (Table 2) are mentioned as follows:
Table 1: Neuro-regenerative agent in cerebral ischemia [23]
|
Neuro-regenerative agents |
Rationale |
Applications |
|
Fibroblast growth factors (FGFs) |
FGF are group of structurally similar polypeptide mitogens, which promote tissue repair, angiogenesis, neurogenesis, axonal growth, embryonic development, and various endocrine signaling pathways. Administration of FGF-2 (based on experimental studies) has shown to increase the number of neurons and markers for neurogenesis. Up-regulation of FGF-2 via adeno-associated viral vectors in the infarct area can increase the number of proliferating cells and motor behaviour. |
MCAO induced ischemic brain injury |
|
Nicotinamide adenine dinucleotide (NAD) |
NAD is a coenzyme of vitamin B3 critical for many biochemical reactions including energy production, ion homeostasis, and biosynthesis of glucose and fatty acids. NAD+ depletion and subsequent ATP loss during/after cerebral ischemia result in energy failure and cell death, this suggests that repletion of NAD+ is beneficial. |
MCAO induced ischemic brain injury |
|
Melatonin (N-acetyl-5-methoxy tryptamine) |
Melatonin plays a crucial role in the regulation of sleep and wake cycles and has been widely used for the treatment of sleep disorders. Also recent studies suggest that melatonin provides other non-sleep/wake cycle related pharmacological effects, such as anti-nitric oxide (NO) production, anti-oxyradicals, and anti-peroxynitrite effects. Oxyradicals, NO, and peroxynitrite play a crucial role in the pathological progression of neuronal cell death following cerebral ischemia, suggesting melatonin use may provide neuroprotection against cerebral ischemia. |
MCAO induced ischemic brain injury; bilateral common carotid artery occlusion induced cerebral ischemia |
|
Resveratrol |
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a poly-phenol found in many plants. Numerous studies show it has multifactorial effects including anti-inflammation and anti-oxidation. Other studies suggest that resveratrol attenuates ischemic brain injury via inhibition of myeloperoxidase levels, pyrin domain-containing 3 inflammasome formation, cerebral TNF-α production and markers for apoptosis, indicating resveratrol has potential for treatment of cerebral ischemia. |
MCAO and bilateral common carotid artery occlusion induced cerebral ischemia |
|
Protein kinase C (PKC) isozymes, δPKC and εPKC |
There is an enhanced expression of δPKC after cerebral ischemia, and subsequent studies suggest that inhibition of δPKC via δPKC specific inhibitor (δV1-1) can alleviate neuronal cell death and CBF derangements, showing the neuroprotective effects of δPKC inhibition after cerebral ischemia. While εPKC (another PKC isozyme) expression is actually enhanced during therapeutic hypothermia and ischemic preconditioning, which suggest εPKC’s has possible neuroprotective role in ischemic brain injury. |
Oxygen and glucose deprivation; ACA and bilateral common carotid artery occlusion induced cerebral ischemia |
|
Pifithrin-α (PFT-α) |
For a study PFT-α (p53 inhibitor) was synthesized to evaluate the therapeutic potentials of p53 inhibition on ischemic brain injury. According to this study, it was observed that PFT-α can reduce neuronal cell death in the CA1 region of the hippocampus, suggesting its use may have therapeutic potential against cerebral ischemia in the near future. Few studies reported that PFT-α can stimulate angiogenesis and neurogenesis after MCAO, while other studies suggest PFT-α reduces infarct volume and neurological and locomotor deficits via vascular endothelial growth factor-mediated pathways. |
MCAO induced ischemic brain injury |
Table 2: Neuro-regenerative factors/therapies in cerebral ischemia [23]
|
Neuro-regenerative factors/therapies |
Rationale |
Applications |
|
Hypothermia |
In a study it was found that hypothermia treatment (at 33 and 30°C) significantly reduced neuronal metabolic demand and glutamate release, ultimately attenuating neuronal cell death in the CA1 region of the hippocampus after cerebral ischemia. Another experiment shows that moderate hypothermia significantly reduces intracranial pressure, cerebral edema, and neurological deficits in patients with severe middle cerebral artery infarction. Further studies reported hypothermia to reduce apoptosis, autophagy, and inflammation, as well as blood-brain barrier leakage and brain metabolism after cerebral ischemia. |
MCAO and bilateral common carotid artery occlusion induced cerebral ischemia; traumatic brain injury; patients with middle cerebral artery infraction |
|
Fatty acids |
Palmitic acid methyl ester (PAME) released from the sympathetic nervous system is a novel vasodilator and CBF mediator. Since hypoperfusion (decrease in CBF) following cerebral ischemia plays a crucial role in the pathological progression of neuronal cell death and neurological deficits, the vasodilatory properties of PAME suggest its therapeutic potential in the treatment against cerebral ischemia. |
MCAO and ACA induced cerebral ischemia |
|
Attenuation of sympathetic nervous system |
Surgical interruption of perivascular sympathetic nerves via decentralization of superior cervical ganglion (a sympathetic ganglion that innervates cerebral arteries) can alleviate ACA-induced hypoperfusion and brain injury. Interruption of cervical sympathetic chain in the superior cervical ganglion has been shown to reduce neurological deficits after aneurysmal subarachnoid haemorrhage in humans. |
ACA induced cerebral ischemia; aneurysmal subarachnoid haemorrhage |
|
Neuro-modulation therapy |
Neuromodulation therapy is a novel technique that utilizes implantable neuromodulatory device/stimulator to deliver electrical or magnetic stimuli directly upon injured neurons. Recent clinical studies suggest that non-invasive brain stimulation via transcranial direct current stimulation (tDCS) or theta burst stimulation (TBS, a neuromodulatory device that provides continuous theta frequency low-intensity stimuli into target brain regions) can facilitate motor and language recovery after chronic stroke. |
MCAO induced cerebral ischemia; patients with ischemic stroke |
|
Traditional Chinese therapies |
Traditional Chinese therapies (i.e., plant-based medicines and acupuncture) are considered novel therapies against stroke/cerebral ischemia due to their multifactorial effects. They can inhibit cerebral ischemia-induced excitotoxicity, inflammation, and apoptosis, while promoting angiogenesis and cerebral blood flow after cerebral ischemia. |
MCAO induced cerebral ischemia; patients with acute stroke |
|
Stem cell therapy |
Stem cells has self-regenerative, differentiating, and multifunctional properties; and can be divided into endogenous and exogenous therapies. Endogenous therapies utilize neurotrophic and growth factors, such as epidermal growth factor, glial cell-derived neurotrophic factor, FGF-2, insulin-like growth factor-1, and brain-derived neurotrophic factor to enhance vascular regeneration and brain synaptic plasticity, while it stimulates the reparative abilities of the endogenous neural stem cells (NSCs) in the injured dentate gyrus and subventricular zone (SVZ), thus reducing lesion size and locomotor deficits. Exogenous therapies use tissue extraction, in vitro cultivation, and subsequent stem cell transplantation into damaged brain regions caused by stroke/cerebral ischemia. |
MCAO induced cerebral ischemia; patients with acute stroke |
What is Cerebroprotein Hydrolysate?
Cerebroprotein hydrolysate is a mixture of peptides and free amino acids extracted from porcine brain tissue which has been proved to be effective in inhibiting microglial activation, neuro-inflammation and free radical formation and it has been shown to promote neuronal sprouting and stimulate neurogenesis [24, 25]. Moreover, it can penetrate biological membranes easily and pass through the blood brain barrier to improve neuronal survivals, regulate neuronal plasticity and repair neurons [26-28]. Hence, cerebroprotein hydrolysate is widely regarded as a potential neurotrophic and neuroprotective drug in treatment of vascular dementia, traumatic brain injuries and ischaemic in clinical [29-31].
Cerebroprotein hydrosylate helps in Neuronal differentiation and protection against ischaemic and neurotoxic lesions. It regulates and improves neuronal metabolism. It reduces excitotoxic damage, blocks over-activation of calcium dependent proteases, and scavenges free oxygen radicals. It has been found in animal studies that early intervention with cerebroprotein hydrosylate reduces blood-brain and blood-cerebrospinal fluid barrier permeability changes, attenuates brain pathology and brain edema, and mitigates functional deficits caused by traumatic brain injury [30]. It improved brain bioelectrical activity, i.e. reduced EEG ratio by increasing fast frequencies and reducing slow activities and also improves cognitive performance in tasks, evaluating attention and memory functions in post-acute traumatic brain injury patients [31].
Mechanism of Action and Pharmacological Effects
It acts by multiple mechanisms viz. [33]:-
Pharmacokinetics
It is given in a dose of 60 -180 mg once daily for 10-20 days. It should be slowly infused in 250 ml saline in 60-120 minutes. Maintenance doses (30 mg) can be given by I.M. route. It should not be mixed with amino acid solutions in the infusion bottle. Doses of antidepressants should be reduced if used with cerebroprotein hydrolysate.
Adverse Effects and Contraindications
Studies have revealed that most of the side effects are minor. Most common side effects include headache, nausea, vertigo, increased sweating, agitation, fever, hallucinations, confusion, and flu like syndrome. Contraindications include hypersensitivity, epilepsy and severe renal impairment. Safety has not been established in pregnancy and lactation.
Drug Interactions
Based on cerebroprotein hydrolysate's pharmacological profile, special attention should be paid to possible additive effects when used in conjunction with anti-depressants or monoamine oxidase inhibitors (MAOIs). In such cases, it is recommended that the dose of the antidepressant is lowered. Cerebroprotein hydrolysate should not be mixed with balanced amino-acid solutions in one infusion [34].
Indications [35]
Cerebroprotein Hydrolysate in Traumatic Brain Injury, Acute Ischemic Stroke, Vascular Dementia, Extrapontine Myelinolysis and Alzheimer ’s disease
There are very few medications that can reduce the functional disability caused by traumatic brain injury. The complex study of cognitive and emotional status, levels of serum serotonin and brain-derived neurotrophic factor (BDNF) performed in 72 patients with acute traumatic brain injury, with a special focus on moderate brain injuries (MBI), treated with cerebrolysin found that cerebrolysin improves outcomes of closed craniocerebral injury by promoting activation of neurotrophic processes [36]. Cerebroprotein hydrolysate-augmented proliferation, differentiation, migration of adult SVZ neural progenitor cells results in increased number of neural progenitor cells and neuroblasts which contribute to neurogenesis. The beneficial effect seen in traumatic brain injury and acute ischaemic stroke may be due to this mechanism. A double-blind, placebo-controlled, randomized study showed that cerebrolysin improves the cognitive function of patients with mild traumatic brain injury (MTBI) at 3rd month after injury, especially for long-term memory and drawing function tested on Mini-Mental Status Examination (MMSE) and Cognitive Abilities Screening Instrument (CASI) scores.
Conclusion
Cerebroprotein hydrolysate is the first drug with neurotrophic factors which are small proteins that exert survival promoting and trophic action on neuronal cells. It consists of short biological peptides, which act like endogenous neurotrophic factors. Neurotrophic activity can be detected up to 24 h after a single injection. It is the only medication indicate in dementias that acts at a neuronal level unlike others that act at neurotransmission and neurotransmitter levels. In our case series, we continued the medications that patients were on and improvement that was not noticed earlier was seen after starting cerebroprotein therapy.
Cerebroprotein hydrolysate is a medication that acts at a brain level and provides us with an effective tool for improving levels of activities of daily living in such patients with various neurological disorders and decreasing their dependence on caregivers though further research in larger populations and clinical trials is warranted. Initial experiences show promising results for cerebroprotein hydrosylate but it is still in its early stages and will require extensive randomized controlled trials before its efficacy is proved.
References
